Methods for inhibiting drug degradation

ABSTRACT

Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters to improve the pharmacokinetics, enhance the bioavailability, and enhance the therapeutic effect of drugs that undergo in vivo degradation by cytochrome P450 enzymes.

This application claims the benefit of U.S. Provisional Application61/030,536 filed Feb. 21, 2008, which is by incorporated by reference.

The technology described herein provides methods of inhibitingcytochrome P450 enzymes. The technology also provides methods ofenhancing the therapeutic effect of drugs that are metabolized bycytochrome P450 enzymes, methods of decreasing the toxic effects ofdrugs that are metabolized to toxic by-products by cytochrome P450enzymes, methods of increasing oral bioavailability of drugs that aremetabolized by cytochrome P450 enzymes, and methods of curing diseasesthat are caused or exacerbated by the activity of cytochrome P450enzymes.

BACKGROUND

Cytochrome P450s (CYP450) are a family of enzymes involved in theoxidative metabolism of both endogenous and exogenous compounds. CYP450enzymes are widely distributed in the liver, intestines and othertissues (Krishna et al., Clinical Pharmacokinetics. 26:144-160, 1994).CYP450 enzymes catalyze the phase I reaction of drug metabolism, togenerate metabolites for excretion. The classification of CYP450s isbased on homology of the amino acid sequence (Slaughter et al The Annalsof Pharmacotherapy 29:619-624, 1995). In mammals, there is over 55%homology of the amino acid sequence of CYP450 subfamilies. Thedifferences in amino acid sequence constitute the basis for aclassification of the superfamily of CYP450 enzymes into families,subfamilies and isozymes.

CYP450 contains an iron cation and is a membrane bound enzyme that cancarry out electron transfer and energy transfer. CYP450, when bound tocarbon monoxide (CO), displays a maximum absorbance (peak) at 450 nm inthe visible spectra, and is therefore called P450 (Omura et al., J.Biol. Chem. 239:2370, 1964).

Over 200 genes encoding CYP450s have been identified, and are dividedamong over 30 gene families. These gene families are organized intosubfamilies, which vary in regulation of gene expression and in aminoacid sequence homology, substrate specificity, catalytic activity, andphysiological role of the encoded enzymes. Representative P450 genes andsubstrates of the encoded enzymes are discussed below.

Listed below are examples of known substrates of members of variousCYP450 subfamilies. See also the discussion in Klassen, ed., Casarettand Doull's Toxicology: The Basic Science of Poisons, McGraw-Hill, 1996,pp. 150 ff. Further information about CYP450 substrates, can be found inGonzales and other review articles cited above. Current informationsources available via the Internet include the “Cytochrome P450Homepage”, maintained by David Nelson, the “Cytochrome P450 Database”,provided by the Institute of Biomedical Chemistry & Center for MolecularDesign, and the “Directory of P450-containing Systems”, provided byKirill N. Degtyarenko and Peter Fabian.

CYP1A1: diethylstilbestrol, 2- and 4-hydroxyestradiol

CYP1A2: acetaminophen, phenacetin, acetanilide (analgesics), caffeine,clozapine (sedative), cyclobenzaprine (muscle relaxant), estradiol,imipramine (antidepressant), mexillitene (antiarrhythmic), naproxen(analgesic), riluzole, tacrine, theophylline (cardiac stimulant,bronchodilator, smooth muscle relaxant), warfarin.

CYP2A6: coumarin, butadiene, nicotine

CYP2A13: nicotine

CYP2B1: phenobarbital, hexobarbital

CYP2C9: NSAIDs such as diclofenac, ibuprofen, and piroxicam; oralhypoglycemic agents such as tolbutamide and glipizide; angiotensin-2blockers such as irbesartan, losartan, and valsartan; naproxen(analgesic); phenytoin (anticonvulsant, antiepileptic);sulfamethoxazole, tamoxifen (antineoplastic); torsemide; warfarin,flurbiprofen

CYP2C19: hexobarbital, mephobarbital, imipramine, clomipramine,citalopram, cycloguanil, the anti-epileptics phenytoin and diazepam,S-mephenytoin, diphenylhydantoin, lansoprazole, pantoprazole,omeprazole, pentamidine, propranolol, cyclophosphamide, progesterone

CYP2D6: antidepressants (imipramine, clomipramine, desimpramine),antipsychotics (haloperidol, perphenazine, risperidone, thioridazine),beta blockers (carvedilol, S-metoprolol, propafenone, timolol),amphetamine, codeine, dextromethorphan, fluoxetine, S-mexiletine,phenacetin, propranolol

CYP2E1: acetaminophen; chlorzoxazone (muscle relaxant), ethanol;caffeine, theophylline; dapsone, general anesthetics such as enflurane,halothane, and methoxyflurane; nitrosamines

CYP3A4: HIV Protease Inhibitors such as indinavir, ritonavir, lopinavir,amprenavir, tipranavir, darunavir, and saquinavir; HIV integraseinhibitors such as elvitegravir, Hepatitis C virus (HCV) proteaseinhibitors, benzodiazepines such as alprazolam, diazepam, midazolam, andtriazolam; immune modulators such as cyclosporine; antihistamines suchas astemizole and chlorpheniramine; HMG CoA Reductase inhibitors such asatorvastatin, cerivastatin, lovastatin, and simvastatin; channelblockers such as diltiazem, felodipine, nifedipine, nisoldipine,nitrendipine, and verapamil; antibiotics such as clarithromycin,erythromycin, and rapamycin; various steroids including cortisol,testosterone, progesterone, estradiol, ethinylestradiol, hydrocortisone,prednisone, and prednisolone; acetaminophen, aldrin, alfentanil,amiodarone, astemizole, benzphetamine, budesonide, carbamazepine,cyclophosphamide, ifosfamide, dapsone, digitoxin, quinidine(anti-arrhythmic), etoposide, flutamide, imipramine, lansoprazole,lidocaine, losartan, omeprazole, retinoic acid, FK506 (tacrolimus),tamoxifen, taxol and taxol analogs such as taxotere, teniposide,terfenadine, buspirone, haloperidol (antipsychotic), methadone,sildenafil, trazodone, theophylline, toremifene, troleandomycin,warfarin, zatosetron, zonisamide.

CYP6A1: fatty acids.

The efficacy of a drug can be dramatically affected by its metabolism inthe body. For drugs that are rapidly metabolized it can be difficult tomaintain an effective therapeutic dose in the body, and the drug oftenmust be given more frequently, in higher dose, and/or be administered ina sustained release formulation. Moreover, in the case of compounds fortreating infectious disease, such as viral or bacterial infections, theinability to maintain an effective therapeutic dose can lead to theinfectious agent becoming drug resistant. Many compounds that havestrong biological efficacy and that would otherwise be potentiallypowerful therapeutics are rendered essentially useless by virtue oftheir short half-lives in vivo. A common pathway of metabolism for drugscontaining lipophilic moieties is via oxidation by one or more CYP450enzymes. These enzymes metabolize a drug to a more polar derivative thatis more readily excreted through the kidney or liver. First passmetabolism refers to the elimination of drugs via liver and intestinalCYP450 enzymes. First pass metabolism can lead to poor drug absorptionfrom the GI tract due to extensive intestinal CYP450 metabolism, lowplasma blood levels due to hepatic CYP450 metabolism, or both. Poor oralbioavailability due to CYP450 metabolism is a major reason for thefailure of drugs candidates in clinical trials. In some instances,metabolic by-products of CYP450 enzymes are highly toxic and can resultin severe side effects, cancer, and even death.

Some examples of the effects of drug metabolism by CYPs include:

Acetaminophen: Ethanol up-regulates CYP2E1, which metabolizesacetaminophen to a reactive quinone. This reactive quinone intermediate,when produced in sufficient amounts, causes liver damage and necrosis.

Sedatives: The sedative phenobarbital (PB) up-regulates several P450genes, including those of the CYP2B and CYP3A subfamilies. Upregulationof these enzymes increases the metabolism and reduces the sedativeeffects of PB and the related sedative hexobarbital.

Antibiotics: The antibiotics rifampicin, rifampin, rifabutin,erythromycin, and related compounds are inducers of the CYP3A4 gene andare substrates of the enzyme product.

Anti-cancer agents: Taxol and taxotere are potent anti-cancer agents.Both drugs are extensively metabolized by CYP3A4 and have poor oralbioavailability. These drugs are only efficacious in parenteralformulations which, due to their poor solubility properties, are highlynoxious to patients.

Nicotine: CYP2A6 and 2A13 convert nicotine, a non-toxic component ofcigarette smoke, into NNK, a highly potent carcinogen that contributesto lung cancer from smoking.

Oral contraceptive/estrogen replacement therapy: Estrogens andestradiols are the active ingredients in oral contraceptives and inhormonal replacement therapies for post-menopausal women. Women who arealso taking antibiotics such as rifampicin or erythromycin, orglucocorticoids such as dexamethasone, or who smoke, risk decreasedefficacy of the estrogenestradiol treatments due to increased metabolismof these compounds by up-regulated CYP3A4 and/or CYP1A2 enzymes.

Dextromethorphan: CYP2D6 metabolizes dextromethrophan to dextrorphan.Individuals who express high levels of CYP2D6 (so-called rapidmetabolizers) do not receive therapeutic benefits from dextromethorphandue to extensive first-pass metabolism and rapid systemic clearance.

Protease Inhibitors: Protease inhibitors and non-nucleoside reversetranscriptase inhibitors currently indicated for use in treatment of HIVor HCV are typically good substrates of cytochrome P450 enzymes; inparticular, they are metabolized by CYP3A4 enzymes (see e.g., Sahai,AIDS 10 Suppl 1:S21-5, 1996) with possible participation by CYP2D6enzymes (Kumar et al., J. Pharmacol. Exp. Ther. 277(1):423-31, 1996). Inaddition to being good CYP3A4 substrates, some protease inhibitors arereported to also be inhibitors of this enzyme, while some non-nucleosidereverse transcriptase inhibitors, such as nevirapine and efavirenz, areinducers of CYP3A4 (see e.g., Murphy et al., Expert Opin. Invest Drugs59: 1183-99, 1996).

Human CYP450 isozymes are widely distributed among tissues and organs(Zhang et al., Drug Metabolism and Disposition. 27:804-809, 1999). Withthe exception of CYP1A1 and CYP2A13, most human CYP450 isozymes arelocated in the liver, but are expressed at different levels (Waziers J.Pharmacol. Exp. Ther. 253: 387, 1990). A solution to the problem of drugdegradation and first-pass metabolism is to control the rate of drugmetabolism. When the rates of drug absorption and metabolism reach asteady state, a maintenance dose can be delivered to achieve a desireddrug concentration that is required for drug efficacy. Certain naturalproducts have been shown to increase bioavailability of a drug. Forexample, the effect of grapefruit juice on drug pharmacokinetics is wellknown. See Edgar et al., Eur. J. Clin. Pharmacol. 42:313, (1992); Lee etal., Clin. Pharmacol. Ther. 59:62, (1996); Kane et al., Mayo ClinicProc. 75:933, (2000). This effect of grapefruit juice is due to thepresence of natural P450-inhibiting components. Other compounds alsohave been used for inhibition of P450. For example, the HIV-1 proteaseinhibitor Ritonavir® is now more commonly prescribed for use incombination with other, more effective, HIV protease inhibitors becauseof its ability to “boost” those other compounds by inhibitingP450-mediated degradation.

Present methods of inhibiting cytochrome P450 enzymes are not whollysatisfactory because of toxicity issues, high cost, and other factors.For example, using ritonavir to inhibit cytochrome P450 is not desirablein disorders other than HIV infection. It is apparent, therefore, thatnew and improved methods of inhibiting cytochrome P450 enzymes aregreatly to be desired. In particular, methods where an inhibitor can beco-administered with another biologically active compound that ismetabolized by cytochrome P450 enzymes are highly desirable.

SUMMARY OF THE TECHNOLOGY

The technology provides methods of inhibiting cytochrome P450 enzymes.The technology also provides methods of enhancing the therapeutic effectof drugs that are metabolized by cytochrome P450 enzymes, methods ofdecreasing the toxic effects of drugs that are metabolized to toxicby-products by cytochrome P450 enzymes, methods of increasing oralbioavailability of drugs that are metabolized by cytochrome P450enzymes, and methods of curing diseases that are caused or exacerbatedby the activity of cytochrome P450 enzymes.

An advantage of the technology is that it provides improved inhibitorsof cytochrome P450 enzymes. Another advantage is that it provides amethod of controlling the pharmacokinetic properties of drugs. Anotheradvantage is that it helps control the rate of metabolism of drugs.Another advantage is that it controls the degradation of drugs. Anotheradvantage is that it enhances the bioavailability of drugs. Anotheradvantage is that it enhances the efficacy of drugs. Another advantageis that it boosts the efficacy of certain drugs so that the drugs can beadministered at a lower concentration or dosage thereby reducing theirtoxicity. Another advantage is that these properties can lower theoverall cost associated with the treatment of disorders.

More particularly, in one aspect, the technology provides a method ofinhibiting cytochrome P450 monooxygenase by administering a compoundrepresented by a formula:

X-A-B-X′

where:

X is a lipophilic group containing from 1 to 12 carbon atoms optionallycontaining from 1 to 3 heteroatoms independently selected from the groupconsisting of O, S, and N,

A is selected from the group consisting of a bond, —OCON(R2)-,—S(O)_(n)N(R2)-, —CON(R2)-, —COCO(NR2)-, —N(R2)CON(R2)-,—N(R2)S(O)_(n)N(R2)-, N(R2)CO or —N(R2)COO—;

B is —(CG₁G₂)_(m)-, where m is 0-6 and where G₁ and G₂ are the same ordifferent and where each G₁ and G₂ independently is selected from thegroup consisting of a bond, H, halo, haloalkyl, OR, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aralkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, and optionally substituted heterocycloalkylwhere each optional substitution independently is selected from thegroup consisting of alkyl, halo, cyano, CF₃, OR, C₃-C₇ cycloalkyl, C₅-C₇cycloalkenyl, R6, OR2, SR2, N(R2)₂, OR3, SR3, NR2R3, OR6, SR6, andNR2R6, and where G₁ and G₂, together with the atoms to which they areattached, optionally may form a 3-7-membered carbocyclic or heterocyclicring containing up to three heteroatoms selected from the groupconsisting of N, S and O, and where the ring optionally may besubstituted with up to 3 R7 moieties,

X′ is

where M is selected from the group consisting of: a bond, OC(R8)_(q),—CO—, —SO_(n)—, —O—, —O—CO—, —N(D)-SO_(n)—, —N(D)-CO_(n)—,—N(D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or —CO_(n)—N(D)-(R8)_(q)-,

where M can be linked in either orientation with respect to thebenzofuran ring,

where D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,heteroaryl, heteroaralkyl, aralkyl, or O-alkyl, where D optionally issubstituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl;

where R is H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl;

where each R2 is independently selected from the group consisting of H,C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, and heterocycloalkyl each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

or each R2 is independently selected from the group consisting of C₁-C₆alkyl; substituted by aryl or heteroaryl; which groups optionally aresubstituted with one or more substituents selected from the groupconsisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR;

R3 is C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, or heterocyclo; which groups optionally are substitutedwith one or more substituents selected from the group consisting ofhalo, OR2, R2-OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, oxo, ═N—OR2, ═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂,═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂, and ═NNR2S(O)_(n)(R2);

R6 is aryl or heteroaryl, where the aryl or heteroaryl optionally aresubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO₂, CN,CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂,S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2,NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, OC(O)R2, OC(S)R2, OC(O)N(R2)₂,and OC(S)N(R2)₂;

R7 is H, oxo, C₁-C₁₂ alkyl; C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or heterocycloalkyl, each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

R8 is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl;

where n=1-2, and q=0-1,

where the benzene ring of the benzofuran moiety may optionally bysubstituted by up to three substituents independently selected from thegroup consisting of R2, halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, andNRPO_(n)OR, where the up to three substituents do not form a ringbetween any adjacent carbon atoms of the benzene ring, and with theproviso that the compound does not contain a basic aliphatic aminefunction and does not contain a carboxylic acid group.

In a specific embodiment, there is provided a method of inhibitingcytochrome P450 monooxygenase in a patient by administering to thepatient a compound represented by the formula:

X-A-B-X′

where:

X is a lipophilic group containing from 1 to 12 carbon atoms optionallycontaining from 1 to 3 heteroatoms independently selected from the groupconsisting of O, S, and N,

A is —OCON(R2)-, —S(O)_(n)N(R2)-, —CON(R2)-, —COCO(NR2)-,—N(R2)CON(R2)-, —N(R2)S(O)_(n)N(R2)-, N(R2)CO or —N(R2)COO—;

B is —(CG₁G₂)_(m)-, where m is 2-6 and where G₁ and G₂ are the same ordifferent and where each G₁ and G₂ independently is selected from thegroup consisting of a bond, H, halo, haloalkyl, OR, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aralkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, and optionally substituted heterocycloalkylwhere each optional substitution independently is selected from thegroup consisting of alkyl, halo, cyano, CF₃, OR, C₃-C₇ cycloalkyl, C₅-C₇cycloalkenyl, R6, OR2, SR2, N(R2)₂, OR3, SR3, NR2R3, OR6, SR6, andNR2R6, and where G₁ and G₂, together with the atoms to which they areattached, optionally may form a 3-7-membered carbocyclic or heterocyclicring containing up to three heteroatoms selected from the groupconsisting of N, S and O, and where the ring optionally may besubstituted with up to 3 R7 moieties,

X′ is

where J is selected from:

—N(D)-SO_(n)—, —N(D)-CO_(n)—, —N(D)-(R8)_(q)-, —N(CO-D)-(R8)_(q)-,—N(SO_(n)-D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or—CO_(n)—N(D)-(R8)_(q)-,

wherein D is selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl,O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl,O-heteroaralkyl, O-aralkyl, N(R2)-alkyl, N(R2)-cycloalkyl,N(R2)-cycloalkylalkyl, N(R2)-heterocycloalkyl,N(R2)-heterocycloalkylalkyl, N(R2)-heteroaralkyl, N(R2)-aralkyl, whereinD optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl, orS-alkyl;

where R is H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl;

where each R2 is independently selected from the group consisting of H,C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, and heterocycloalkyl each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

or each R2 is independently selected from the group consisting of C₁-C₆alkyl; substituted by aryl or heteroaryl; which groups optionally aresubstituted with one or more substituents selected from the groupconsisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR;

R3 is C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, or heterocyclo; which groups optionally are substitutedwith one or more substituents selected from the group consisting ofhalo, OR2, R2-OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, oxo, ═N—OR2, ═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂,═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂, and ═NNR2S(O)_(n)(R2);

R6 is aryl or heteroaryl, where the aryl or heteroaryl optionally aresubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO₂, CN,CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂,S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2,NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, OC(O)R2, OC(S)R2, OC(O)N(R2)₂,and OC(S)N(R2)₂;

R7 is H, oxo, C₁-C₁₂ alkyl; C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or heterocycloalkyl, each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

R8 is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl;

where n=1-2, and

where q=0-1.

In another aspect, X may be alkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, or heteroaralkyl; where Xoptionally is substituted with one or more substituents selected fromthe group consisting of C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,C₅-C₈ cycloalkenyl, heterocyclo; halo, OR, ROH, R-halo, NO₂, CN,CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂,N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R,NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂,═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and ═NNRS(O)_(n)(R). In one embodiment,X may be selected from the group consisting of alkyl, cycloalkyl, aryl,aralkyl, heteroaryl, and heteroaralkyl. X optionally is substituted withone or more substituents selected from the group consisting of halo, OR,ROH, R-halo, CN, CO_(n)R, CON(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂,N(R)CO_(n)R, NRS(O)_(n)R, oxo, and ═N—OR.

In other aspects, G₁ and G₂ may be the same or different andindependently are selected from the group consisting of a bond, H, OR,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aralkyl, optionally substituted heteroaryl, andoptionally substituted heteroaralkyl. In specific embodiments, G₁ and G₂do not form a ring, or at least one G₁ and at least one G₂ form a ring.G₁ and G₂ may be different and, in certain embodiments, neither G₁ norG₂ is OH.

In other aspects G1 and G2 are selected from the group consisting of H,O-alkyl, alkyl, optionally substituted aryl and optionally substitutedaralkyl.

In the embodiments above, J may be

—N(D)-SO_(n)—, —N(D)-CO_(n)—, —N(D)-(R8)_(q)-, —N(CO-D)-(R8)_(q)-,—N(SO_(n)-D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or—CO_(n)—N(D)-(R8)_(q)-.

In the embodiments above, D may be hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl,O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl,O-heteroaralkyl, O-aralkyl, N(R2)-alkyl, N(R2)-cycloalkyl,N(R2)-cycloalkylalkyl, N(R2)-heterocycloalkyl,N(R2)-heterocycloalkylalkyl, N(R2)-heteroaralkyl, N(R2)-aralkyl, whereinD optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl, orS-alkyl.

In any of the embodiments above, when X is a 5-7 membered non-aromaticmonocyclic heterocycle, optionally fused or bridged with one or more 3-7membered non-aromatic monocyclic heterocycle to form a polycyclicsystem, wherein any of said heterocyclic ring systems contains one ormore heteroatoms selected from O, N, S, and P, and

when

B is

where U is selected from optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted cycloalkyl, or optionallysubstituted aralkyl, and

then J cannot be —N(D)-SO_(n)— or —N(D)-CO_(n)—.

In the methods described above, the cytochrome P450 monoxygenase may beCYP3A4 or CYP3A5.

In other embodiments, the compound used in the methods described abovedoes not inhibit HIV protease.

In specific embodiments, the patient may be suffering from chronic pain,depression, epilepsy, psychosis, inflammation, cancer, cardiovasculardisease, diabetes, neurodegenerative disease such as Alzheimer'sdisease, and/or infection, for example, infection with ahepatitis-causing virus or HIV.

In other embodiments, the compound is administered substantiallycontemporaneously with a drug where efficacy of the drug is compromiseddue to degradation by cytochrome P450 monooxygenase. The drug may be,for example, Cyclosporine, Tacrolimus (FK506), Sirolimus (rapamycin),Indinavir, Ritonavir, Saquinavir, Felodipine, Isradipine, Nicardipine,Nisoldipine, Nimodipine, Nitrendipine, Nifedipine, Verapamil, Etoposide,Tamoxifen, Vinblastine, Vincristine, Taxol, Atorvastatin, Fluvastatin,Lovastatin, Pravastatin, Simvastatin, Terfenadine, Loratadine,Astemizole, Alfentanil, Carbamazepine, Azithromycin, Clarithromycin,Erythromycin, Itraconazole, Rifabutin, Lidocaine, Cisapride, Sertraline,Pimozide, Triazolam, Anastrazole, Busulfan, Corticosteroids(dexamethasone, methylprednisone and prednisone), Cyclophosphamide,Cytarabine, Docetaxel, Doxorubicin, Erlotinib, Exemestane, Gefitinib,Idarubicin, Ifosphamide, Imatinib mesylate, Irinotecan, Ketoconazole,Letrozole, Paclitaxel, Teniposide, Tretinoin, Vinorelbine, quinidine,alprazolam, diazepam, midazolam, nelfinavir, chlorpheniramine,amlodipine, diltiazem, lercanidipine, cerivastatin, estradiol,hydrocortisone, progesterone, testosterone, alfentanyl, aripiprazole,cafergot, caffeine, cilostazol, cocaine, codeine, dapsone,dextromethorphan, domperidone, eplerenone, fentanyl, finasteride,gleevec, haloperidol, irinotecan, Levo-Alpha Acetyl Methadol (LAAM),methadone, nateglinide, odansetron, propranolol, quinine, salmeterol,sildenafil, trazodone, vincristine, zaleplon, zolpidem, ixabepilone,Agenerase (APV), Aptivus (TPV), Crixivan (IDV), Invirase (SQV), Lexiva(FPV), Prezista (DRV), Reyataz (ATV) Viracept (NFV), Elvitegravir,Selzentry, Vicriviroc, Telaprevir, Telithromycin, tandospirone orbuspirone.

The details of one or more examples are set forth in the accompanyingreaction schemes and description. Further features, aspects, andadvantages of the technology will become apparent from the description,the schemes, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows examples of cytochrome P450 inhibitors of the invention.These examples are merely illustrative and not limiting of the presentinvention. All of the compounds shown have a Ki that is better than 100nM.

DETAILED DESCRIPTION

The technology provides methods of inhibiting cytochrome P450 (CYP)enzymes. More particularly, the technology provides methods forenhancing the therapeutic effect of drugs in which the efficacy iscompromised due to degradation mediated by cytochrome P450. The methodsinclude administering compounds or pharmaceutical compositionscontaining the compounds in any therapeutic regimen where one or moreprimary drugs is metabolized by a CYP. The compounds or pharmaceuticalcompositions can be administered when the primary drug either becomesinactive or is converted to a toxic metabolite due to metabolism by aCYP. The compounds or compositions can inhibit or reduce the rate ofdegradation of drugs that are effective against a variety of diseasesand that are degraded by one or more cytochrome P450 enzymes. Uponco-administration, the compounds and compositions can, for example,maintain intracellular concentrations of the drugs at a therapeuticlevel for a sustained period of time. The methods are useful, forexample, in treating a variety of disorders such as, cardiac arrhythmia,depression, psychosis, chronic pain, and infections such as HIV or HCV.The compounds or compositions can be administered either alone or incombination with drugs such as analgesics, anti-depressants,anti-psychotics, antibiotics, anti-arrhythmics, steroids, anesthetics,muscle relaxants, cardiac stimulants, NSAIDs, anti-epileptics, orprotease inhibitors, such as HIV or HCV protease inhibitors. The drugsmay be, for example, The drug may be, for example, Cyclosporine,Tacrolimus (FK506), Sirolimus (rapamycin), Indinavir, Ritonavir,Saquinavir, Felodipine, Isradipine, Nicardipine, Nisoldipine,Nimodipine, Nitrendipine, Nifedipine, Verapamil, Etoposide, Tamoxifen,Vinblastine, Vincristine, Taxol, Atorvastatin, Fluvastatin, Lovastatin,Pravastatin, Simvastatin, Terfenadine, Loratadine, Astemizole,Alfentanil, Carbamazepine, Azithromycin, Clarithromycin, Erythromycin,Itraconazole, Rifabutin, Lidocaine, Cisapride, Sertraline, Pimozide,Triazolam, Anastrazole, Busulfan, Corticosteroids (dexamethasone,methylprednisone and prednisone), Cyclophosphamide, Cytarabine,Docetaxel, Doxorubicin, Erlotinib, Exemestane, Gefitinib, Idarubicin,Ifosphamide, Imatinib mesylate, Irinotecan, Ketoconazole, Letrozole,Paclitaxel, Teniposide, Tretinoin, Vinorelbine, quinidine, alprazolam,diazepam, midazolam, nelfinavir, chlorpheniramine, amlodipine,diltiazem, lercanidipine, cerivastatin, estradiol, hydrocortisone,progesterone, testosterone, alfentanyl, aripiprazole, cafergot,caffeine, cilostazol, cocaine, codeine, dapsone, dextromethorphan,domperidone, eplerenone, fentanyl, finasteride, gleevec, haloperidol,irinotecan, Levo-Alpha Acetyl Methadol (LAAM), methadone, nateglinide,odansetron, propranolol, quinine, salmeterol, sildenafil, trazodone,vincristine, zaleplon, zolpidem, ixabepilone, Agenerase (APV), Aptivus(TPV), Crixivan (IDV), Invirase (SQV), Lexiva (FPV), Prezista (DRV),Reyataz (ATV) Viracept (NFV), Elvitegravir, Selzentry, Vicriviroc,Telaprevir, Telithromycin, tandospirone or buspirone.

In particular, the technology provides a method of inhibiting cytochromeP450 monooxygenase by administering to a patient, a compound representedby a formula:

X-A-B-X′

where:

X is a lipophilic group containing from 1 to 12 carbon atoms optionallycontaining from 1 to 3 heteroatoms independently selected from the groupconsisting of O, S, and N,

A is selected from the group consisting of a bond, —OCON(R2)-,—S(O)_(n)N(R2)-, —CON(R2)-, —COCO(NR2)-, —N(R2)CON(R2)-,—N(R2)S(O)_(n)N(R2)-, N(R2)CO or —N(R2)COO—;

B is (CG₁G₂)_(m)-, where m is 0-6 and where G₁ and G₂ are the same ordifferent and where each G₁ and G₂ independently is selected from thegroup consisting of a bond, H, halo, haloalkyl, OR, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aralkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, and optionally substituted heterocycloalkylwhere each optional substitution independently is selected from thegroup consisting of alkyl, halo, cyano, CF₃, OR, C₃-C₇ cycloalkyl, C₅-C₇cycloalkenyl, R6, OR2, SR2, N(R2)₂, OR3, SR3, NR2R3, OR6, SR6, andNR2R6, and where G₁ and G₂, together with the atoms to which they areattached, optionally may form a 3-7-membered carbocyclic or heterocyclicring containing up to three heteroatoms selected from the groupconsisting of N, S and O, and where the ring optionally may besubstituted with up to 3 R7 moieties,

X′ is

where M is selected from the group consisting of: a bond, OC(R8)_(q),—CO—, —SO_(n)—, —O—, —O—CO—, —N(D)-SO_(n)—, —N(D)-CO_(n)—,—N(D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or CO—N(D)-(R8)_(q)-,

where M can be linked in either orientation with respect to thebenzofuran ring,

where D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,heteroaryl, heteroaralkyl or aralkyl, O-alkyl, where D optionally issubstituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl;

where R is H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl;

where each R2 is independently selected from the group consisting of H,C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, and heterocycloalkyl each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

or each R2 is independently selected from the group consisting of C₁-C₆alkyl; substituted by aryl or heteroaryl; which groups optionally aresubstituted with one or more substituents selected from the groupconsisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR;

R3 is C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, or heterocyclo; which groups optionally are substitutedwith one or more substituents selected from the group consisting ofhalo, OR2, R2-OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, oxo, ═N—OR2, ═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂,═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂, and ═NNR2S(O)_(n)(R2);

R6 is aryl or heteroaryl, where the aryl or heteroaryl optionally aresubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO₂, CN,CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂,S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2,NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, OC(O)R2, OC(S)R2, OC(O)N(R2)₂,and OC(S)N(R2)₂;

R7 is H, oxo, C₁-C₁₂ alkyl; C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or heterocycloalkyl, each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

R8 is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl;

where n=1-2, and q=0-1,

where the benzene ring of the benzofuran moiety may optionally bysubstituted by up to three substituents independently selected from thegroup consisting of R2, halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, andNRPO_(n)OR, where the up to three substituents do not form a ringbetween any adjacent carbon atoms of the benzene ring, and with theproviso that the compound does not contain a basic aliphatic aminefunction and does not contain a carboxylic acid group.

In a specific embodiment, the invention provides methods of inhibitingcytochrome P450 monooxygenase in a patient by administering to thepatient a compound represented by the formula:

X-A-B-X′

where:

X is a lipophilic group containing from 1 to 12 carbon atoms optionallycontaining from 1 to 3 heteroatoms independently selected from the groupconsisting of O, S, and N,

A is —OCON(R2)-, —S(O)_(n)N(R2)-, —CON(R2)-, —COCO(NR2)-,—N(R2)CON(R2)-, —N(R2)S(O)_(n)N(R2)-, N(R2)CO or —N(R2)COO—;

B is —(CG₁G₂)_(m)-, where m is 2-6 and where G₁ and G₂ are the same ordifferent and where each G₁ and G₂ independently is selected from thegroup consisting of a bond, H, halo, haloalkyl, OR, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aralkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, and optionally substituted heterocycloalkylwhere each optional substitution independently is selected from thegroup consisting of alkyl, halo, cyano, CF₃, OR, C₃-C₇ cycloalkyl, C₅-C₇cycloalkenyl, R6, OR2, SR2, N(R2)₂, OR3, SR3, NR2R3, OR6, SR6, andNR2R6, and where G₁ and G₂, together with the atoms to which they areattached, optionally may form a 3-7-membered carbocyclic or heterocyclicring containing up to three heteroatoms selected from the groupconsisting of N, S and O, and where the ring optionally may besubstituted with up to 3 R7 moieties,

X′ is

where J is selected from:

—N(D)-SO_(n)—, —N(D)-CO_(n)—, —N(D)-(R8)_(q)-, —N(CO-D)-(R8)_(q)-,—N(SO_(n)-D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or—CO_(n)—N(D)-(R8)_(q)-,

where D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl,O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl,O-heteroaralkyl, O-aralkyl, N(R2)-alkyl, N(R2)-cycloalkyl,N(R2)-cycloalkylalkyl, N(R2)-heterocycloalkyl,N(R2)-heterocycloalkylalkyl, N(R2)-heteroaralkyl, N(R2)-aralkyl, whereinD optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl, orS-alkyl;

where R is H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl;

where each R2 is independently selected from the group consisting of H,C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, and heterocycloalkyl each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)_(n)(R);

or each R2 is independently selected from the group consisting of C₁-C₆alkyl; substituted by aryl or heteroaryl; which groups optionally aresubstituted with one or more substituents selected from the groupconsisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR;

R3 is C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, or heterocyclo; which groups optionally are substitutedwith one or more substituents selected from the group consisting ofhalo, OR2, R2-OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R2, NR2S(O)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2,oxo, ═N—OR2, ═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂, ═NNR2C(O)_(n)R2,═NNR2S(O)_(n)N(R2)₂, and ═NNR2S(O)_(n)(R2);

R6 is aryl or heteroaryl, where the aryl or heteroaryl optionally aresubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO₂, CN,CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂,S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2,NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, OC(O)R2, OC(S)R2, OC(O)N(R2)₂,and OC(S)N(R2)₂;

R7 is H, oxo, C₁-C₁₂ alkyl; C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or heterocycloalkyl, each further optionally substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)(R);

R8 is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl;

where n=1-2, and

where q=0-1.

In another aspect, X may be alkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, or heteroaralkyl; where Xoptionally is substituted with one or more substituents selected fromthe group consisting of C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,C₅-C₈ cycloalkenyl, heterocyclo; halo, OR, ROH, R-halo, NO₂, CN,CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂,N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R,NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂,═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and ═NNRS(O)_(n)(R). In one embodiment,X may be selected from the group consisting of alkyl, cycloalkyl, aryl,aralkyl, heteroaryl, and heteroaralkyl. X optionally is substituted withone or more substituents selected from the group consisting of halo, OR,ROH, R-halo, CN, CO_(n)R, CON(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂,N(R)CO_(n)R, NRS(O)_(n)R, oxo, and ═N—OR.

In other aspects, G₁ and G₂ may be the same or different andindependently are selected from the group consisting of a bond, H, OR,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aralkyl, optionally substituted heteroaryl, andoptionally substituted heteroaralkyl. In specific embodiments, G₁ and G₂do not form a ring, or at least one G₁ and at least one G₂ form a ring.G₁ and G₂ may be different and, in certain embodiments, neither G₁ norG₂ is OH.

In other aspects G1 and G2 are selected from the group consisting of H,O-alkyl, alkyl, optionally substituted aryl and optionally substitutedaralkyl.

In the embodiments above, J may be

—N(D)-SO_(n)—, —N(D)-CO_(n)—, —N(D)-(R8)_(q)-, —N(CO-D)-(R8)_(q)-,—N(SO_(n)-D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or—CO_(n)—N(D)-(R8)_(q)-.

In the embodiments above, D may be hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl,O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl,O-heteroaralkyl, O-aralkyl, N(R2)-alkyl, N(R2)-cycloalkyl,N(R2)-cycloalkylalkyl, N(R2)-heterocycloalkyl,N(R2)-heterocycloalkylalkyl, or N(R2)-heteroaralkyl, N(R2)-aralkyl,where D optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl,or S-alkyl.

In the compounds, when X is a 5-7 membered non-aromatic monocyclicheterocycle, optionally fused or bridged with one or more 3-7 memberednon-aromatic monocyclic heterocycle to form a polycyclic system, whereany of the heterocyclic ring systems contains one or more heteroatomsselected from O, N, S, and P, and

when B is

where U is selected from optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted cycloalkyl, or optionallysubstituted aralkyl, then J cannot be —N(D)-SO_(n)— or —N(D)-CO_(n).

In the methods described above, the cytochrome P450 monoxygenase may beCYP3A4 or CYP3A5.

In other embodiments, the compound used in the methods described abovedoes not inhibit HIV protease. In the context of the present invention,a compound is said to not inhibit HIV protease when the Ki of thecompound is greater than about 1 μM. Such a Ki means that the compoundis not clinically useful for inhibiting HIV protease in a patientinfected with HIV.

In specific embodiments, the patient may be suffering from chronic pain,depression, epilepsy, psychosis, inflammation, cancer, cardiovasculardisease, diabetes, neurodegenerative disease, and/or infection, forexample, infection with a hepatitis-causing virus or HIV.

In other embodiments, the compound is administered substantiallycontemporaneously with a drug where efficacy of the drug is compromiseddue to degradation by cytochrome P450 monooxygenase.

This technology also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. The basicnitrogen can be quaternized with any agents known to those of ordinaryskill in the art including, for example, lower alkyl halides, such asmethyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkylsulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; and aralkyl halides including benzyl and phenethylbromides. Water or oil-soluble or dispersible products can be obtainedby such quaternization.

By way of illustration, but not of limitation, an exemplary CYPinhibitor according to the technology has the structure:

In this molecule, D is isobutyl, B is —(CH₂)₃, A is —OCON(n-hexyl)-, andX is t-butyl. Certain CYP inhibitors that contain a hydroxyethylenemoiety are simultaneously HIV protease inhibitors. These compounds alsocan be represented by the formula X-A-B-X′ with the requirement that Bmust contain a hydroxyethylene group, i.e. one G group must be ahydroxyl and an adjacent G group must be H. Typically, a CYP inhibitoris found to exhibit HIV protease inhibitor activity when B has thestructure: —CH(G)CH(OH)CH₂— where G in this instance is not OH, andtypically, though not necessarily, is aralkyl. Advantageously X is abis-tetrahydrofuranyl moiety and A is a urethane linker.

The table below shows examples of various X, A, B and J moieties,although it will be recognized that these examples are merelyillustrative and not limiting of the present invention.

X A B J

The term “pharmaceutically effective amount” or “therapeuticallyeffective amount” or “therapeutic dose” or “efficacious dose” refers toan amount that when administered to a subject is effective in inhibitingcytochrome P450 enough to reduce or prevent the in vivo degradation of aco-administered drug and thereby improve the pharmacokinetics of thedrug and/or boost its efficacy. The term “treating” as used hereinrefers to the alleviation of symptoms of a particular disorder in asubject, such as a human patient, or the improvement of an ascertainablemeasurement associated with a particular disorder. The term“prophylactically effective amount” refers to an amount effective inpreventing an infection, for example an HIV infection, in a subject,such as a human patient. As used herein, a “subject” refers to a mammal,including a human.

The term “co-administered drug” or “drug” refers to a compound given toa patient or subject, which may be a human, for prophylactic ortherapeutic treatment. For example, a drug or a co-administered drug maybe a compound or composition listed in the U.S. Pharmacopeia, or thePhysician's Desk Reference. In specific embodiments a drug orco-administered drug is selected from Cyclosporine, Tacrolimus (FK506),Sirolimus (rapamycin), Indinavir, Ritonavir, Saquinavir, Felodipine,Isradipine, Nicardipine, Nisoldipine, Nimodipine, Nitrendipine,Nifedipine, Verapamil, Etoposide, Tamoxifen, Vinblastine, Vincristine,Taxol, Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Simvastatin,Terfenadine, Loratadine, Astemizole, Alfentanil, Carbamazepine,Azithromycin, Clarithromycin, Erythromycin, Itraconazole, Rifabutin,Lidocaine, Cisapride, Sertraline, Pimozide, Triazolam, Anastrazole,Busulfan, Corticosteroids (dexamethasone, methylprednisone andprednisone), Cyclophosphamide, Cytarabine, Docetaxel, Doxorubicin,Erlotinib, Exemestane, Gefitinib, Idarubicin, Ifosphamide, Imatinibmesylate, Irinotecan, Ketoconazole, Letrozole, Paclitaxel, Teniposide,Tretinoin, Vinorelbine, telithromycin, quinidine, alprazolam, diazepam,midazolam, nelfinavir, chlorpheniramine, amlodipine, diltiazem,lercanidipine, cerivastatin, estradiol, hydrocortisone, progesterone,testosterone, alfentanyl, aripiprazole, buspirone, cafergot, caffeine,cilostazol, cocaine, codeine, dapsone, dextromethorphan, docetaxel,domperidone, eplerenone, fentanyl, finasteride, gleevec, haloperidol,irinotecan, Levo-Alpha Acetyl Methadol (LAAM), methadone, nateglinide,odansetron, propranolol, quinine, salmeterol, sildenafil, terfenadine,trazodone, vincristine, zaleplon, zolpidem, ixabepilone, Agenerase(APV), Aptivus (TPV), Crixivan (IDV), Invirase (SQV), Lexiva (FPV),Prezista (DRV), Reyataz (ATV) Viracept (NFV), Elvitegravir, Selzentry,Vicriviroc, Telaprevir, Telithromycin, tandospirone or buspirone. A drugmay also be a compound that, because of its metabolism in a subject, maynot otherwise be effective for treating a condition in the subjectunless administered with a compound that inhibits CYP activity.

The term “antiretroviral agent” as used herein refers to a compound thatinhibits the ability of a retrovirus to effectively infect a host.Antiretroviral agents can inhibit a variety of process including thereplication of viral genetic materials, or entry of retroviruses intocells. In some embodiments, antiretroviral agents are selected from thegroup consisting of: protease inhibitor, a reverse transcriptaseinhibitor, and a viral fusion inhibitor. In other embodiments theantiretroviral agents are selected from the group consisting of:abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir,zidovudine, elvucitabine, apricitabine, zalcitabine, delavirdine,efavirenz, nevirapine, rilpivirine, etravirine, atazanavir, darunavir,fosamprenavir, indinavir, lopinavir, Kaletra, nelfinavir, ritonavir,saquinavir, tipranavir, enfuvirtide, maraviroc, vicriviroc, raltegravir,elvitegravir, interferon, albuferon, telaprevir, boceprevir, andviramidine.

The term “lipophilic group” as used herein refers to a group that, whena part of a compound, increases the affinity or propensity of thecompound to bind, attach or dissolve in fat, lipid or oil rather thanwater. A measure of the lipophilicity or hydrophobicity of compounds ofthe technology can be calculated using the Hansch equation:

Log 1/C=kP

where C is the concentration of a compound in a given solvent and P isthe hydrophobicity. Details of this method can be obtained from J. Amer.Chem. Soc, 86:5175 (1964) and Drug Design I, edited by E. J. Ariens,Academic Press (1971), both of which are hereby incorporated byreference in their entireties.

Examples of a typical lipophilic group include, but are not limited to,alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, amyl, n-hexyl,n-heptyl, cyclohexyl, cycloheptyl, octyl, nonyl, decyl, undecyl, anddodecyl, alkenes such as ethylene, propylene, butene, pentene, hexene,cyclohexene, heptene, cycloheptene, octene, cyclooctene, nonene, decene,undecene, dodecene, 1,3-butadiene, alkynes such as propyne and butyne,aryls such as phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl,aralkyls such as benzyl, heterocyclyls such as tetrahydrothiophene,dihydrobenzofuran, heteroaryls such as pyrrole, furan, thiophene,pyrazole, thiazole, indole, carbazole, benzofuran, benzothiophene,indazole, benzothiazole, purine, pyridine, pyridazine, pyrazine,triazine, quinoline, acridine, isoquinoline, and phenanthroline.

For small groups containing heteroatom substituents, such as smallheterocycles with a high ratio of heteroatoms to carbon atoms, theintroduction of substituents that reduce the heteroatom to carbon atomratio renders the group lipophilic. For example, a triazole ring can berendered more lipophilic by the introduction of alkyl substituents.Similarly, non-lipophilic substituents such as hydroxy or amido can berendered lipophilic by introducing additional carbon atoms, for exampleby exchanging a hydroxymethyl group to a hydroxybenzyl group, or byexchanging a carboxamido group to a dialkyl carboxamido group.

The term “substituted”, whether preceded by the term “optionally” ornot, and substitutions contained in formulas of this technology, includethe replacement of one or more hydrogen radicals in a given structurewith the radical of a specified substituent. When more than one positionin a given structure can be substituted with more than one substituentselected from a specified group, the substituents can be either the sameor different at every position (for example, in the moiety —N(R2)(R2),the two R2 substituents can be the same or different). In someembodiments where a structure can be optionally substituted, any or allof the hydrogens present may be replaced by substituents. In someembodiments, 0-3 hydrogen atoms may be replaced. In other embodiments,0-1 hydrogen atoms may be replaced. Substituents advantageously enhancecytochrome P450 inhibitory activity in permissive mammalian cells, orenhance the deliverability by improving solubility characteristics, orpharmacokinetic or pharmacodynamic profiles as compared to theunsubstituted compound. Combinations of substituents and variablesenvisioned by this technology are limited to those that result in theformation of stable compounds. Enhancements to cytochrome P450inhibitory activity, deliverability and pharmacokinetic parametersachieved by the addition of substituents may result in synergisticenhancement of a compound's action and suitability for use in one ormore applications.

The term “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture, formulation, andadministration to a mammal by methods known in the art. Typically, suchcompounds are stable at a temperature of 40° C. or less, in the absenceof moisture or other chemically reactive conditions, for at least aweek. In one embodiment the compounds have less than 5% degradationafter storage in the dark at 40° C. or less, in the absence of moistureor other chemically reactive conditions. In another embodiment compoundshave less than 10% degradation after storage in the dark at 40° C. orless, in the absence of moisture or other chemically reactiveconditions.

The term “alkyl”, alone or in combination with any other term, refers toa straight-chain or branched-chain saturated aliphatic hydrocarbonradical containing the specified number of carbon atoms, or where nonumber is specified, advantageously from 1 to about 12 or 1 to 15 carbonatoms. Examples of alkyl radicals include, but are not limited to:methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isoamyl, n-hexyl and the like.

The term “alkenyl”, alone or in combination with any other term, refersto a straight-chain or branched-chain mono- or poly-unsaturatedaliphatic hydrocarbon radical containing the specified number of carbonatoms, or where no number is specified, advantageously from 2-6 or 2-10carbon atoms. Alkenyl groups include all possible E and Z isomers unlessspecifically stated otherwise. Examples of alkenyl radicals include, butare not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl,pentenyl, hexenyl, hexadienyl and the like.

The term “alkynyl,” alone or in combination with any other term, refersto a straight-chain or branched-chain hydrocarbon radical having one ormore triple bonds containing the specified number of carbon atoms, orwhere no number is specified, advantageously from 2 to about 10 carbonatoms. Examples of alkynyl radicals include, but are not limited to,ethynyl, propynyl, propargyl, butynyl, pentynyl and the like.

The term “alkoxy” refers to an alkyl ether radical, where the term“alkyl” is as defined above. Examples of suitable alkyl ether radicalsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The terms “alkylamino” or “dialkylamino” include amino radicalssubstituted by one or two alkyl groups, where the term “alkyl” isdefined above, and the alkyl groups can be the same or different.Examples of suitable alkylamino and dialkylamino radicals include, butare not limited to, methylamino, ethylamino, isopropylamino,dimethylamino, methylethylamino, ethylbutylamino and the like.

The term “hydroxyalkyl” refers to an alkyl radical as defined above inwhich one of the hydrogen atoms is replaced by hydroxy group. Examplesof suitable hydroxyalkyl radicals include, but are not limited to,hydroxymethyl, 2-hydroxypropyl and the like.

The term “alkoxyalkyl” refers to an alkyl radical as defined above inwhich one of the hydrogen atoms is replaced by an alkoxy radical asdefined above.

The terms “aminoalkyl”, “alkylaminoalkyl” or “dialkylaminoalkyl” refersto an alkyl radical as defined above in which one of the hydrogen atomsis replaced by an amino or “alkylamino” or “dialkylamino” radical asdefined above.

The term “halo” or “halogen” includes fluorine, chlorine, bromine oriodine. Halogens may be limited to fluorine, chlorine, and bromine orfluorine and chlorine.

The term “haloalkyl” includes alkyl groups with one or more hydrogensreplaced by halogens.

The term “thioalkyl” includes alkyl radicals having at least one sulfuratom, where alkyl has the significance given above. An example of athioalkyl is CH₃SCH₂. The definition also encompasses the correspondingsulfoxide and sulfone of this thioalkyl CH₃S(O)CH₂ and CH₃S(O)₂CH₂respectively. Unless expressly stated to the contrary, the terms “—SO₂—”and “—S(O)₂—” as used herein include sulfone or sulfone derivative(i.e., both appended groups linked to the S), and not a sulfinate ester.

The terms “carboalkoxy” or “alkoxycarbonyl” include alkyl esters of acarboxylic acid. Examples of “carboalkoxy” or “alkoxycarbonyl” radicalsinclude, but are not limited to ethoxycarbonyl (or carboethoxy), Boc (ort-butoxycarbonyl), Cbz (or benzyloxycarbonyl) and the like.

The term “alkanoyl” includes acyl radicals derived from analkanecarboxylic acid. Examples of alkanoyl radicals include, but arenot limited to acetyl, propionyl, isobutyryl and the like.

The term “aryl,” alone or in combination with any other term, refers toa carbocyclic aromatic radical (such as phenyl or naphthyl) containing aspecified number of carbon atoms. In some embodiments aryl radicalscontain from 6-16 carbon atoms, and in other embodiments aryl radicalscontain from 6 to 14 or 6-10 carbon atoms in their ring structures. Arylradicals may be optionally substituted with one or more substituentsselected from alkyl, alkoxy, (for example methoxy), nitro, halo, amino,mono or dialkylamino, carboalkoxy, cyano, thioalkyl, alkanoyl,carboxylate, and hydroxy. Examples of aryl radicals include, but are notlimited to phenyl, p-tolyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl,indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.

The term “aralkyl”, alone or in combination, includes alkyl radicals asdefined above in which one or more hydrogen atoms is replaced by an arylradical as defined above. Examples of aralkyl radicals include, but arenot limited to benzyl, 2-phenylethyl and the like. The alkyl radical ofa aralkyl group may be an alkyl radical having 1 to 4, 1 to 6, 1 to 8, 2to 4, 2 to 6 or 2 to 8 carbon atoms.

The term “aralkanoyl” includes acyl radicals derived from anaryl-substituted alkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, (1-naphthyl)acetyl,4-methoxyhydrocinnamoyl, and the like.

The term “aroyl” includes acyl radicals derived from an aromaticcarboxylic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl,6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamido)-2-naphthoyl, and the like.

The term “arylsulfonyl” includes sulfonyl radicals derived from anaromatic sulfonic acid such as benzenesulfonyl, 4-chlorobenzenesulfonyl,1-naphthalenesulfonyl, 2-naphthalenesulfonyl, and the like.

The term “carbocycle” refers to a non-aromatic, stable 3- to 8-memberedcarbon ring which can be saturated, mono-unsaturated orpoly-unsaturated. The carbocycle can be attached at any endocycliccarbon atom which results in a stable structure. In some embodiments,carbocycles having 5-7 carbons may be employed, whereas in otherembodiments carbocycles having 5 or 6 carbon atoms may be employed.

The term “cycloalkyl”, alone or in combination, includes alkyl radicalswhich contain from about 3 to about 8 carbon atoms and are cyclic.Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like.

The term “cycloalkenyl” alone or in combination includes alkenylradicals as defined above which contain about 3-8 carbon atoms and arecyclic.

In some embodiments, carbocycle, cycloalkyl or cycloalkenyl groupscontain 3 or 4 carbon atoms in their ring structure. In otherembodiments of carbocycles, cycloalkyl or cycloalkenyl groups contain 5or 6 carbon atoms in their ring structure. In still other embodiments ofcarbocycles, cycloalkyl or cycloalkenyl groups contain 7 or 8 carbonatoms in their ring structure.

The term “cycloalkyl”, alone or in combination, includes alkyl radicalswhich contain from about 3 to about 8 carbon atoms and are cyclic.Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like.

The term “heterocyclyl” or “heterocyclo” or “heterocycloalkyl” refers toa stable 3-7 membered monocyclic heterocycle or 8-11 membered bicyclicheterocycle which is either saturated or partially unsaturated, andwhich can be optionally benzofused if monocyclic and which is optionallysubstituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo,and the like, and/or on a secondary nitrogen atom (i.e., —NH—) by alkyl,aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, arylsulfonyl, phenyl orphenylalkyl or on a tertiary nitrogen atom (i.e., +N—) by oxido andwhich is attached via a carbon atom. Each heterocycle consists of one ormore carbon atoms and from one to four heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur. As used herein, theterms “nitrogen and sulfur heteroatoms” include oxidized forms ofnitrogen and sulfur, and the quaternized form of any basic nitrogen. Aheterocyclyl radical can be attached at any endocyclic carbon orheteroatom which results in the creation of a stable structure.Preferred heterocycles include 5-7 membered monocyclic heterocycles, and8-10 membered bicyclic heterocycles. Examples of such groups areimidazolinyl, imidazolidinyl, indazolinyl, perhydropyridazyl,pyrrolinyl, pyrrolidinyl, piperidinyl, pyrazolinyl, piperazinyl,morpholinyl, thiamorpholinyl, thiazolidinyl, thiamorpholinyl sulfone,oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, tetrahydropyranyl,tetrahydrofuranyl, dioxolyl, dioxinyl, benzodioxolyl, dithiolyl,tetrahydrothienyl, sulfolanyl, dioxanyl, dioxolanyl,tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl,dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.

The term “heteroaryl” refers to stable 5-6 membered monocyclic or 8-11membered bicyclic or 13-16 membered tricyclic aromatic heterocycleswhere heterocycle is as defined above. In some embodiments, heteroatomspresent in heteroaryl radicals are limited to one or more independentlyselected O, N or S atoms. Non-limiting examples of such groups includeimidazolyl, quinolyl, isoquinolyl, indolyl, indazolyl, pyridazyl,pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, quinoxalinyl, pyrimidinyl,furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl,benzofuranyl, oxazolyl, benzoxazolyl, benzimidazolyl, benzthiazolyl,isoxazolyl, isothiazolyl, furazanyl, thiadiazyl, acridinyl,phenanthridinyl, and benzocinnolinyl.

The term “heterocycloalkylalkyl” refers to an alkyl radical as definedabove which is substituted by a heterocycloalkyl radical as definedabove. The alkyl radical of a heterocycloalkylalkyl group may be analkyl radical having 1 to 4, 1 to 6, 1 to 8, 2 to 4, 2 to 6 or 2 to 8carbon atoms.

The term “heteroaralkyl” alone or in combination, includes alkylradicals as defined above in which one or more hydrogen atom is replacedby a hetoroaryl group as defined above. The alkyl radical of aheteroaralkyl group may be an alkyl radical having 1 to 4, 1 to 6, 1 to8, 2 to 4, 2 to 6 or 2 to 8 carbon atoms.

As used herein, the compounds of this technology (e.g., compounds of theformula X-A-B-X′) are defined to include pharmaceutically acceptablederivatives or prodrugs thereof. A “pharmaceutically acceptablederivative or prodrug” includes a pharmaceutically acceptable salt,ester, salt of an ester, or other derivative of a compound of thistechnology which, upon administration to a recipient, is capable ofproviding (directly or indirectly) a compound of this technology.Particularly favored derivatives and prodrugs are those that increasethe bioavailability of the compounds of this technology when suchcompounds are administered to a mammal (e.g., by allowing an orallyadministered compound to be more readily absorbed into the blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies. Examples of prodrugs of hydroxy containing compounds are aminoacid esters or phosphonate or phosphate esters that can be cleaved invivo hydrolytically or enzymatically to provide the parent compound.These have the advantage of providing potentially improved solubility.

The compounds of this technology (e.g., compounds of the formulaX-A-B-X′) can contain one or more asymmetric carbon atoms and thus occuras racemates and racemic mixtures, single enantiomers, diastereomericmixtures and individual diastereomers. All such isomeric forms of thesecompounds are expressly included in the technology described herein.Each stereogenic carbon can be of the R or S configuration. Although thespecific compounds exemplified in this application can be depicted in aparticular stereochemical configuration, compounds having either theopposite stereochemistry at any given chiral center or mixtures thereofare also envisioned. Thus, the compounds provided herein may beenantiomerically pure, or be stereoisomeric or diastereomeric mixtures.

It is also to be understood that the compounds provided herein may havetautomeric forms. All such tautomeric forms are included within thescope of the instant disclosure. For example, a 3-enamino-2-oxindolewhere the amino group of the enamine has a hydrogen substituent has thetautomeric form of a 3-imino-2-hydroxyindole.

Also included in the present application are one or more of the variouspolymorphs of the compounds. A crystalline compound disclosed in thepresent application may have a single or may have multiple polymorphs,and these polymorphs are intended to be included as compounds of thepresent application. Also, where a single polymorph is noted, thepolymorph may change or interconvert to one or more differentpolymorphs, and such polymorph or polymorph mixtures are included in thepresent application.

Preparation of Compounds

The compounds can be prepared according to synthetic methods known inthe art set forth, for example, in U.S. Pat. No. 6,319,946 to Hale etal., W02008022345A2 (Eissenstat et al.), and in J. Med. Chem. 36:288-291 (1993), the disclosures of which are incorporated herein byreference in their entireties, together with procedures of the typedescribed below. Reactions and processes for obtaining the compounds,particularly the formation of ester and amide linkages, may also befound in treatises and text, including, but not limited to, AdvancedOrganic Synthesis, 4th Edition, J. March, John Wiley & Sons, 1992 orProtective Groups in Organic Synthesis 3rd Edition, T. W. Green & P. G.M. Wuts, John Wiley & Sons, 1999, each of which is hereby incorporatedby reference.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Syntheses, Volumes 1-85 (John Wiley and Sons);Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals(Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-71(John Wiley and Sons), Advanced Organic Synthesis, 4th Edition, J.March, John Wiley & Sons, 1992, and Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989).

Protective groups, such as those described in Protective Groups inOrganic Synthesis 3rd Edition, T. W. Green & P. G. M. Wuts, John Wiley &Sons, 1999 may be employed for a variety of purposes in the preparationof compounds encompassed by this disclosure. They may be employed tocontrol the number or placement of substituents, or to protectfunctionalities that are otherwise unstable to reaction conditionsemployed for the introduction or modification of other substituents in amolecule. Where employed, such protective groups may be removed bysuitable means. Alternatively, where the protective group is desirablein the product they may be introduced and not removed.

In one reaction series, some compounds of the formula X-A-B-X′ may beprepared by the condensation of hydroxyethylamine A withbenzofuran-5-sulfonyl chloride provided compound 36. This material canbe selectively O-alkylated in the presence of base and an alkylatingagent such as iodomethane to provide compound 5. See Barrish, et al. J.Med. Chem. 1758-1768 (1994). Further alkylation on the urethane nitrogencan be accomplished using excess base and alkylating agent. Removal ofthe Boc group under acidic conditions such as trifluoroacetic acidprovides the amine which is subject to condensation with acid chlorides,anhydrides, sulfonyl chlorides, chloroformates, carbamoyl chloride,isocyanates and the like to provide the corresponding amide,sulfonamide, urethane, or urea. Alternatively, reductive amination ofthe amine with an aldehyde under acidic conditions can provide thesecondary amine which can be subjected to similar condensation reactionsto give the N-alkyl products (e.g., N-alkyl amide).

Other amines besides isobutylamine can be used to ring open the epoxideleading to different N-substituted sulfonamides as the products.

Homologation of Boc-phenylalaninol using a mesylation, cyanide,reduction, reductive alkylation protocol provided Boc-diamine 224, whichwas treated with benzofuran-5-sulfonyl chloride as above. See Lim etal., Bioorg. Med. Chem. Lett, 1913-1916 (2004), Dallaire et al.Tetrahedron Lett 5129-5132 (1998), Mecozzi et al., J. Org. Chem.8264-8267(2001). Alternatively the amine from the reduction can first besulfonylated, followed by N-alkylation on the sulfonamide nitrogen inthe presence of a strong base. Additional base and alkylating agent canprovide alkylation of the urethane nitrogen. The Boc group can beremoved under acidic conditions either on either the NH or N-alkylintermediate and the products further elaborated as above bycondensation with acid chlorides, anhydrides, sulfonyl chlorides,chloroformates, carbamoyl chloride, or isocyanates. Alternatively theethylene diamine analogs of these compounds can be prepared by reactingthe activated phenylalaninol with azide instead of cyanide followed byreduction as in Rosenberg, et al., J. Med. Chem. 1582-1590 (1990).Elaboration of this core is as above.

The benzyl group in the core can be replaced by a benzyloxymethyl groupby reducing the commercially available doubly protectedBoc-Cbz-diaminobutyric acid analog to give the alcohol, removing the Cbzprotecting group and sulfonylating the resulting amine as above. SeeWebber et al., J. Med. Chem. 2786-2805 (1998), Catalano, et al., Bioorg.Med. Chem. Lett., 275-278 (2004). Alkylating the hydroxy group using astrong base such as sodium hydride and an alkylating agent providesethers such as compound 12. These can be further elaborated as in theexamples above.

Alternatively compounds without branching in the diamine core can beprepared by taking the well known Boc-diamines, and condensing withbenzofuransulfonyl chloride. See Fiedler, et al.; Helv. Chim. Acta1511-1519 (1993), Chatterjee, et al., Bioorg. Med. Chem. Lett.,(2603-2606) 1999, Saari, et al., J. Med. Chem. 3132-3138 (1991). Theseproducts can be N-alkylated on the sulfonamide nitrogen and thenoptionally on the urethane nitrogen and further elaborated similarly toabove. Alternatively the primary amine can be reductively aminated usingan aldehyde under reducing conditions and then condensed withbenzofuransulfonyl chloride to provide similar products.

Assessment of Compounds

The potency of the compounds can be measured using assays, for example,an in vitro fluorometric assay. Typically, the ability of a testcompound to inhibit P450 is assayed by determining the concentration ofthe test compound required to decrease the rate of metabolism of a CYPsubstrate (also referred to herein as reference compound) by half. TheCYP substrate can be, for example, dibenzylfluorescein. The ability of atest compound to inhibit the rate of metabolism of a reference compoundby half is known as the IC₅₀ value. Human liver microsomes can be usedfor this purpose. Test compounds can be diluted with a suitable solvent,such as acetonitrile, in wells of a microtiter plate. Known cytochromeP450 inhibitors such as ritonavir and ketoconazole can be used asreferences. A suitable buffer solution and NADPH or an NADPH generatingsystem such as, for example, G6P dehydrogenase can be used. After mixingthe inhibitors with the buffer and NADPH system, the plates can beincubated for a suitable time at a suitable temperature. A solutioncontaining human liver microsomes can be added. A buffer containing afluorogenic substrate, such as dibenzylfluorescein, can be added and theplates allowed to incubate for a suitable time at a suitabletemperature. The IC₅₀ values for the test compounds can be measured bydetermining the amount of fluorescence in each well and analyzing thevalues using commercially available software programs such as, forexample, Grafit® (Erithacus Software Ltd., Surrey, U.K.).

Increasing the Half-Life of Therapeutics by Preventing their Metabolismby Cytochrome P450 Enzymes

(Use of Compounds of the Technology for “Boosting”)

CYP P450 enzymes are responsible for the metabolic degradation of avariety of drug molecules, thus disturbing their pharmacokinetics andreducing their bioavailabilty. Where CYP enzymes contribute to themetabolism of compounds, compositions that can inhibit CYP enzymes canimprove the pharmacokinetics and bioavailability of such drugs.

In certain embodiments, the technology provides methods for inhibitingcytochrome P450 monooxygenase by administering to a patient one or morecompounds described herein. The compound can function as a potentcytochrome P450 inhibitor and can improve the pharmacokinetics of a drug(or a pharmaceutically acceptable salt thereof) which is metabolized bycytochrome P450 monooxygenase. The compound or its pharmaceuticallyacceptable salt can be administered by itself or in combination withanother drug. When administered in combination, the two therapeuticagents (e.g., a compound of the formula X-A-B-X′ and a drug) can beformulated as separate compositions which are administered at the sametime or different times, or the two therapeutic agents can beadministered as a single composition.

The compounds of the technology are effective for inhibiting a varietyof CYP enzymes. In particular, many of the compounds are highly potentinhibitors of CYP3A4, which is responsible for degrading manypharmaceutically important drugs. Use of the compounds of the technologytherefore permits reduced rates of drug degradation and consequentlyextended durations of action in vivo. Consequently, these compounds areuseful for “boosting” the activities of a variety of drugs, including,but not limited to, HIV protease inhibitors by inhibitingCYP3A4-mediated degradation of those inhibitors.

Drugs which are metabolized by cytochrome P450 monooxygenase and whichbenefit from coadministration with a compound of the technology include,but are not limited to, the immunosuppressants cyclosporine, FK-506 andrapamycin, the chemotherapeutic agents taxol and taxotere, theantibiotic clarithromycin and the HIV protease inhibitors A-77003,A-80987, indinavir, saquinavir, amprenavir, nelfinavir, fosamprenavir,lopinavir, atazanavir, darunavir, tipranavir, DMP-323, XM-450, BILA 2011BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629(N,N-dimethylglycyl-N-(2-hydroxy-3-(((4-methoxyphenyl)sulphonyl)(2-methylpropyl)amino)-1-(phenylmethyl)propyl)-3-methyl-L-valinamide),PPL-100, SPI-256 and KNI-272.

In other examples, the drug may be a tyrosine kinase inhibitor, such asGleevec (imatinib), Erlotinib, Sorafenib, Sunitinib, dasitinib,lapatinib, and the like. Other kinase inhibitors, such asserinethreonine kinase inhibitors, also may be “boosted.” Suitablekinase inhibitors for boosting also are described in Keri et al.;“Signal Transduction Therapy with Rationally Designed KinaseInhibitors,” Current Signal Transduction Therapy, 1, 67-95 67 (2006).The drug may also be an HSP90 inhibitor such as geldanamycin,herbimycin, and others, as described by Workman et al.: “Drugging thecancer chaperone HSP90: Combinatorial therapeutic exploitation ofoncogene addiction and tumor stress” Workman, Ann N Y Acad Sci,1113:202-216 (2007). In other examples, the drug may be an inhibitor ofHCV NS3 protease, NS4a cofactor, NS4B, NS5a replicase or NS5Bpolymerase. Drugs for treating HIV include, in addition to HIV proteaseinhibitors, inhibitors of CD4-gp120 interaction, CCR5 and CRCX4coreceptors, and inhibitors of the LEDGF-integrase interaction.

Protease inhibitors and non-nucleoside reverse transcriptase inhibitorscurrently indicated for use in treatment of HIV or HCV are typicallygood substrates of cytochrome p450 enzymes; in particular, they aremetabolized by CYP3A4 enzymes (see e.g., Sahai, AIDS 10 Suppl 1:S21-5,1996) with possible participation by CYP2D6 enzymes (Kumar et al., J.Pharmacol. Exp. Ther. 277(1):423-31, 1996). The compounds describedherein can block the action and up-regulation of these enzymes, thusreducing the metabolism of the protease inhibitors, allowing for lowerdoses and reduction of sometimes serious side effects.

Some embodiments described herein are directed to a method for improvingthe pharmacokinetics of an HIV protease inhibitor (or a pharmaceuticallyacceptable salt thereof) which is metabolized by cytochrome P450monooxygenase. The methods comprising coadministering a compound of thetechnology or a pharmaceutically acceptable salt or co-crystal thereof.Such a combination of a compound of the technology described herein or apharmaceutically acceptable salt or co-crystal thereof and an HIVprotease inhibitor or a pharmaceutically acceptable salt thereof whichis metabolized by cytochrome P450 monooxygenase is useful for inhibitingHIV protease in humans and is also useful for inhibition, treatment orprophylaxis of an HIV infection or AIDS (acquired immune deficiencysyndrome) in humans. When administered in combination, the twotherapeutic agents can be formulated as separate compositions which areadministered at the same time or different times, or the therapeuticagents can be administered as a single composition. In some embodimentsthe HIV protease inhibitors are selected from A-77003, A-80987,amprenavir atazanavir, darunavir, fosamprenavir, indinavir, lopinavir,nelfinavir, ritonavir, saquinavir, tipranavir, DMP-323, XM-450, BILA2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151,SC-629,(N,N-dimethylglycyl-N-(2-hydroxy-3-(((4-methoxyphenyl)sulphonyl)(2-methylpropyl)amino)-1-(phenylmethyl)propyl)-3-methyl-L-valinamide),PPL-100, SPI-256 or KNI-272.

Methods of Administration of Compounds

The compounds of the technology can be administered in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. Included among such acid salts, for example, are the following:acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Other pharmaceutically acceptable salts include salts with an inorganicbase, organic base, inorganic acid, organic acid, or basic or acidicamino acid. Inorganic bases which form pharmaceutically acceptable saltsinclude alkali metals such as sodium or potassium, alkali earth metalssuch as calcium and magnesium, aluminum, and ammonia. Organic baseswhich form pharmaceutically acceptable salts include trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine. Inorganic acids which formpharmaceutically acceptable salts include hydrochloric acid, hydroboricacid, nitric acid, sulfuric acid, and phosphoric acid. Organic acidsappropriate to form salts include formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid. Basic amino acids usedto form salts include arginine, lysine and ornithine. Acidic amino acidsused to form salts include aspartic acid and glutamic acid.

The compounds described herein may also be prepared and administered asa composition comprising a co-crystals with other compounds (co-crystalformers). “Co-crystal” as used herein means a crystalline materialcomprised of two or more unique solids at room temperature, eachcontaining distinctive physical characteristics, such as structure,melting point and heats of fusion. Co-crystals are described, forexample, in U.S. Pub. No.: 20070026078 A1, which is incorporated byreference in its entirety. They are also described in N. A. Meanwell,Annual Reports in Medicinal Chemistry, Volume 43, 2008, and D. P.McNamara, Pharmaceutical Research, Vol. 23, No. 8, 2006, which isincorporated by reference in its entirety.

The technology also contemplates compositions which can be administeredorally or non-orally in the form of, for example, granules, powders,tablets, capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions, by mixing these effective components,individually or simultaneously, with pharmaceutically acceptablecarriers, excipients, binders, diluents or the like.

As a solid formulation for oral administration, the composition can bein the form of powders, granules, tablets, pills and capsules. In thesecases, the compounds can be mixed with at least one additive, forexample, sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran,starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum,gum arabic, gelatins, collagens, casein, albumin, synthetic orsemi-synthetic polymers or glycerides. These formulations can contain,as in conventional cases, further additives, for example, an inactivediluent, a lubricant such as magnesium stearate, a preservative such asparaben or sorbic acid, an anti-oxidant such as ascorbic acid,tocopherol or cysteine, a disintegrator, a binder, a thickening agent, abuffer, a sweetener, a flavoring agent and a perfuming agent. Tabletsand pills can further be prepared with enteric coating.

Examples of liquid preparations for oral administration includepharmaceutically acceptable emulsions, syrups, elixirs, suspensions andsolutions, which can contain an inactive diluent, for example, water.

As used herein, “non-orally” includes subcutaneous injection,intravenous injection, intramuscular injection, intraperitonealinjection or instillation. Injectable preparations, for example, sterileinjectable aqueous suspensions or oil suspensions, can be prepared byknown procedures in the fields concerned, using a suitable dispersant orwetting agent and suspending agent. The sterile injections can be, forexample, a solution or a suspension, which is prepared with a non-toxicdiluent administrable non-orally, such as an aqueous solution, or with asolvent employable for sterile injection. Examples of usable vehicles oracceptable solvents include water, Ringer's solution and an isotonicaqueous saline solution. Further, a sterile non-volatile oil can usuallybe employed as solvent or suspending agent. A non-volatile oil and afatty acid can be used for this purpose, including natural or syntheticor semi-synthetic fatty acid oil or fatty acid, and natural or syntheticmono- or di- or tri-glycerides.

The pharmaceutical compositions can be formulated for nasal aerosol orinhalation and can be prepared as solutions in saline, and benzylalcohol or other suitable preservatives, absorption promoters,fluorocarbons, or solubilizing or dispersing agents.

Rectal suppositories can be prepared by mixing the drug with a suitablevehicle, for example, cocoa butter and polyethylene glycol, which is inthe solid state at ordinary temperatures, in the liquid state attemperatures in intestinal tubes and melts to release the drug.

The pharmaceutical composition can be easily formulated for topicaladministration with a suitable ointment containing one or more of thecompounds suspended or dissolved in a carrier, which include mineraloil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, topical formulations can be formulated with a lotion orcream containing the active compound suspended or dissolved in acarrier. Suitable carriers include mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetaryl alcohol, 2-octyldodecanol,benzyl alcohol and water.

In some embodiments, the pharmaceutical compositions can include α-, β-,or γ-cyclodextrins or their derivatives. In certain embodiments,co-solvents such as alcohols can improve the solubility and/or thestability of the compounds in pharmaceutical compositions. In thepreparation of aqueous compositions, addition salts of the compounds canbe suitable due to their increased water solubility.

Appropriate cyclodextrins are α-, β-, or γ-cyclodextrins (CDs) or ethersand mixed ethers thereof where one or more of the hydroxy groups of theanhydroglucose units of the cyclodextrin are substituted with C₁-C₆alkyl, such as methyl, ethyl or isopropyl, e.g., randomly methylatedβ-CD; hydroxy C₁₋₆ alkyl, particularly hydroxyethyl, hydroxypropyl orhydroxybutyl; carboxy C₁-C₆alkyl, particularly carboxymethyl orcarboxyethyl; C₁-C₆alkyl-carbonyl, particularly acetyl; C₁-C₆alkyloxycarbonylC₁-C₆alkyl, or carboxyC₁-C₆alkyloxyC₁-C₆alkyl,particularly carboxymethoxypropyl or carboxyethoxypropyl;C₁-C₆alkylcarbonyloxyC₁-C₆alkyl, particularly 2-acetyloxypropyl.Especially noteworthy as complexants and/or solubilizers are β-CD,randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

The term “mixed ether” denotes cyclodextrin derivatives where at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxypropyl and hydroxyethyl.

The compounds can be formulated in combination with a cyclodextrin or aderivative thereof as described in U.S. Pat. No. 5,707,975. Although theformulations described therein are with antifungal active ingredients,they are equally relevant for formulating compounds (e.g., compounds ofthe formula X-A-B-X′), and composition comprising compounds of thatformula described herein. The formulations described therein areparticularly suitable for oral administration and comprise an antifungalas active ingredient, a sufficient amount of a cyclodextrin or aderivative thereof as a solubilizer, an aqueous acidic medium as bulkliquid carrier and an alcoholic co-solvent that greatly simplifies thepreparation of the composition. The formulations can also be renderedmore palatable by adding pharmaceutically acceptable sweeteners and/orflavors.

Other convenient ways to enhance the solubility of the compounds of thetechnology in pharmaceutical compositions are described in WO 9405263,WO 9842318, EP-A-499,299 and WO 9744014, all incorporated herein byreference.

In some embodiments, the compounds can be formulated in a pharmaceuticalcomposition comprising a therapeutically effective amount of particlesconsisting of a solid dispersion comprising a compound of formula I, andone or more pharmaceutically acceptable water-soluble polymers.

The term “solid dispersion” defines a system in a solid state comprisingat least two components, where one component is dispersed more or lessevenly throughout the other component or components. When the dispersionof the components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermodynamics, such a solid dispersion is referred to as “a solidsolution”.

Solid solutions are preferred physical systems because the componentstherein are usually readily bioavailable to the organisms to which theyare administered.

The term “solid dispersion” also comprises dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase.

The water-soluble polymer in the particles is conveniently a polymerthat has an apparent viscosity of 1 to 100 mPa*s when dissolved in a 2%aqueous solution at 20 C.

Preferred water-soluble polymers are hydroxypropyl methylcelluloses(HPMC). HPMC having a methoxy degree of substitution from about 0.8 toabout 2.5 and a hydroxypropyl molar substitution from about 0.05 toabout 3.0 are generally water soluble. Methoxy degree of substitutionrefers to the average number of methyl ether groups present peranhydroglucose unit of the cellulose molecule. Hydroxypropyl molarsubstitution refers to the average number of moles of propylene oxidewhich have reacted with each anhydroglucose unit of the cellulosemolecule.

The particles as defined hereinabove can be prepared by first preparinga solid dispersion of the components, and then optionally grinding ormilling that dispersion. Various techniques exist for preparing soliddispersions including melt-extrusion, spray-drying andsolution-evaporation.

It can further be convenient to formulate the compounds in the form ofnanoparticles which have a surface modifier adsorbed on the surfacethereof in an amount sufficient to maintain an effective averageparticle size of less than 1000 nm. Useful surface modifiers arebelieved to include those which physically adhere to the surface of theantiretroviral agent but do not chemically bond to the antiretroviralagent.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

The compounds can also be incorporated in hydrophilic polymers andapplied as a film over many small beads, thus yielding a compositionwith good bioavailability which can conveniently be manufactured andwhich is suitable for preparing pharmaceutical dosage forms for oraladministration. The beads comprise a central, rounded or spherical core,a coating film of a hydrophilic polymer and an antiretroviral agent anda seal-coating polymer layer. Materials suitable for use as cores arepharmaceutically acceptable and have appropriate dimensions andfirmness. Examples of such materials are polymers, inorganic substances,organic substances, saccharides and derivatives thereof. The route ofadministration can depend on the condition of the subject, co-medicationand the like.

Dosages of the compounds and compositions described herein are dependenton age, body weight, general health conditions, sex, diet, doseinterval, administration routes, excretion rate, combinations of drugsand conditions of the diseases treated, while taking these and othernecessary factors into consideration. Generally, dosage levels ofbetween about 10 μg per day to about 5000 mg per day, preferably betweenabout 25 mg per day to about 1000 mg per day of the compound are usefulfor the inhibition of CYP enzymes. Typically, the pharmaceuticalcompositions of this technology will be administered from about 1 toabout 3 times per day or alternatively, as a continuous infusion.Alternatively, sustained release formulations, may be employed,Sustained release formulations include, but are not limited to,transdermal or iontophoretic patches, osmoitic devices, or sustainedrelease tablets or suppositories that generally employ expandable orerodible polymer compositions. Such administrations can be used as achronic or acute therapy.

The amount of active ingredient(s) that can be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. A typicalpreparation will contain from about 5% to about 95% active compound(w/w). In some embodiments, such preparations contain from about 20% toabout 80% active compound.

While these dosage ranges can be adjusted by a necessary unit base fordividing a daily dose, as described above, such doses are decideddepending on the diseases to be treated, conditions of such diseases,the age, body weight, general health conditions, sex, diet of thepatient then treated, dose intervals, administration routes, excretionrate, and combinations of drugs, while taking these and other necessaryfactors into consideration. For example, a typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 10% to about 80% active compound.The desired unit dose of the composition of this technology isadministered once or multiple times daily.

In some embodiments, the technology contemplates compositions andformulations comprising one or more of the compounds in combination withone or more other drugs that can be metabolized or degraded by CYP.

The CYP inhibitors of this technology can be administered to a patienteither as a single agent (for use with a separate dose of another drug)or in a combined dosage form with at least one other drug. Additionaldrugs also can be used to increase the therapeutic effect of thesecompounds.

The compounds of this technology can be administered to patients beingtreated with a drug that is metabolized by a CYP enzyme. Such drugsinclude, but are not limited to, anesthetics such as ropivacaine,enflurane, halothane, isoflurane, methoxyflurane, and sevoflurane;antiarrhythmics such as mexiletine; antidepressants such asamitriptyline, clomipramine, fluvoxamine, bupropion, and imipramine;anti-epileptics such as diazepam, phenytoin, S-mephenytoin, andphenobarbitone; antihistamines such as astemizole, chlorpheniramine, andterfenidine; antipsychotics such as clozapine, olanzapine, andhaloperidol; beta blockers such as carvedilol, S-metoprolol,propafenone, and timolol; calcium channel blockers such as amlodipine,diltiazem, felodipine, lercanidipine, nifedipine, nisoldipine,nitrendipine, and verapamil; hypoglycemic agents such as tolbutamide andglipizide; immune modulators such as cyclosporine and tacrolimus; musclerelaxants such as cyclobenzaprine, tizanidine, and carisoprodol;steroids such as estradiol; antimigraine agents such as zolmitriptan;agents used to treat breathing aliments such as zileuton andtheophylline; agents used to treat Alzheimer's disease such as tacrine;agents used to treat pain such as naproxen and acetaminophen; agentsused to treat amyotrophic lateral sclerosis such as riluzole;anti-nausea agents such as ondansetron; chemotherapeutics such aspaclitaxel, ifosfamide, and cyclophosphamide; loop diuretics such astorsemide; antidiabetic agents such as repaglinide; statin, such ascerivastatin; antimalarial agents such as amodiaquine; proton pumpinhibitors such as lansoprazole, omeprazole, pantoprazole, andrabeprazole; and sulfonylureas such as glyburide, glibenclamide,glipizide, glimepiride, and tolbutamide. Patients being treated with aprotease inhibitor, a reverse transcriptase inhibitor, a viral fusioninhibitor, or an integrase inhibitor can also be treated with thecompounds provided herein. The CYP inhibitors provided herein can beco-administered with the other drug(s). The compounds of the technologycan also be administered in combination with other cytochrome P450inhibitors (e.g., ritonavir), immunomodulators (e.g., bropirimine,anti-human alpha interferon antibody, IL-2, and HE-2000) withantibiotics (e.g., pentamidine isothiorate) cytokines (e.g., Th2),modulators of cytokines, chemokines or the receptors thereof (e.g.,CCR5) or hormones (e.g., growth hormone) to ameliorate, combat, oreliminate infections as therapeutically appropriate.

CYP inhibitors can also be used as standalone therapeutics forCYP-mediated diseases, or as prophylactic agents for preventing theproduction of toxic metabolites. For example, an inhibitor of CYP2A6 or2A13 can be used to ameliorate the carcinogenic effects of tobaccousage.

Such combination therapy in different formulations can be administeredsimultaneously, separately or sequentially. The CYP inhibitors can beadministered prior to administration of the other drug to reduce CYPlevels and minimize degradation of the drug. In specific embodiments,the CYP inhibitor is administered, 30 minutes, 1 hour, four hours,twelve hours or twenty four hours prior to initial administration of theother drug. The CYP inhibitors tend to have a long half in vivo,presumably as a result of inhibiting their own metabolism. This meansthat once treatment has begun, the CYP inhibitor may be administeredless frequently than the drug, although the skilled artisan willrecognize that different administration regiments may be needed inspecific situations. In certain instances, CYP inhibitors can alsoinduce expression of CYPs and the skilled artisan will appreciate thatin such circumstances, administration of the CYP inhibitor may need tobe more frequent. Alternatively, such combinations can be administeredas a single formulation, whereby the active ingredients are releasedfrom the formulation simultaneously or separately.

The following examples illustrate further the technology but, of course,should not be construed in any way of limiting its scope.

EXAMPLES Example 1 Assay of IC₅₀ for CYP Inhibitors: DeterminationsUsing Dibenzylfluorescein Metabolism by Human Liver Microsomes

A microtiter plate based, fluorometric assay was used for thedetermination of the concentration of a test compound that will decreaseby half the maximal rate of dibenzylfluorescein, a CYP3A4 substrate,metabolism by human liver microsomes. The assay was run as described byCrespi et al. Anal. Biochem. 248:188-90 (1997).

Test compounds were diluted in acetonitrile in wells of a polypropylenemicrotiter plate (Denville Scientific, Inc. Metuchen, N.J.). Three foldserial dilutions of the test article were made from the first well intothe next seven wells of a row. Two wells of each row were used forpositive controls containing no test compound and two for negativescontaining 500 μM Ritonavir in acetonitrile. Test compounds inacetonitrile (0.004 mL) were added to wells of a micro titer plate(Catalog No. 3598, Corning Costar, Cambridge, Mass.) containing asolution (0.096 mL) of 0.2 M KPO₄ Buffer (pH 7.4) and a NADPH generatingsystem (2.6 mM NADP, 6.6 mM glucose-6-phosphate, 3.3 mM MgCl₂ and 0.8Units/mL G6P dehydrogenase (BD/Gentest, Woburn, Mass.). The plates wereincubated for 10 minutes at 37° C. prior to addition of 0.1 mL ofpre-warmed 0.1 mg/mL human liver microsomes (Xeno Tech, LLC, Lenexa,Kans.) in 0.2 M KPO₄ Buffer containing 2 μM dibenzylfluorescein(BDGentest, Woburn, Mass.). The plates were incubated for 10 minutes at37° C. and the reaction are stopped by the addition of 0.075 mL of 2NNaOH. Plates were incubated at 37° C. for 1 hours prior to determiningthe amount of fluorescence in each well with a fluorescent plate reader(Spectra Max Gemini XS, Molecular Devices) at excitation/emissionwavelengths of 485 and 538 nm (25 nm), respectively. Data were exportedand analyzed using GraFit® (Erithacus Software Ltd., Surrey, U.K.). Thebackground corrected data is fit to a 2-parameter equation for thedetermination of the IC₅₀.

Example 2 Synthetic Methods

The following experimental protocols and transformations areillustrative of the methods used to synthesize the compounds of thetechnology. Syntheses of the compounds below are exemplified, althoughthe skilled artisan will recognize that these exemplary methods are ofgeneral applicability.

hydroxyethylamine A

Example 2a

(1-Benzyl-2-hydroxy-3-isobutylamine-propyl)-carbamic acid tert-butylester (SM A, 10.08 g, 30 mmol, 1.0 equiv.) and 1-benzofuran-5-sulfonylchloride (SM B, 9.74 g, 45 mmol, 1.5 equiv.) were dissolved indichloromethane (100 mL). To the solution was added triethylamine (8.36mL, 60 mmol, 2.0 equiv.) at room temperature. The mixture was stirred atthe same temperature for 2.5 h, after which time the reaction wasquenched through the addition of 0.5 N hydrochloric acid aqueoussolution (50 mL). The phases were separated and then the organic layerwas sequentially washed with 5% sodium bicarbonate (50 mL) and water (50mL). The final organic solution was dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified by recrystallizationfrom ethyl acetatehexane (3090, v/v) to afford a white solid, 13.09 g,m.p. 121.1-122.4° C. The filtrate was concentrated and the residue waspurified on silica gel (0-50% ethyl acetate in hexane) to afford 1.13 gadditional target compound. Yield 14.22 g (92%). MS 1055 (2MNa)⁺, 539(MNa)⁺, 417 (M-BOC)⁺ and 575 (AcOM)⁻. Purity 97% (HPLC).

Example 2b

A 250 mL three-neck round-bottom flask was equipped with a magneticstirbar, an argon inlet adapter and an air outlet adapter connected to abubbler. The flask was charged with compound 36 (12.38 g, 24 mmol, 1.0equiv.), anhydrous THF (96 mL), and methyl iodide (3.0 mL, 48 mmol, 2.0equiv.) under argon. The mixture was cooled to 0° C. and treated withsodium hydride (1.92 g, 48 mmol, 2.0 equiv.) in portions. The resultingsuspension was stirred for 3 h while the reaction was allowed to returnto ambient temperature. Then 100 ml of water was added. The clearsolution was concentrated in vacuo to remove the most of THF and wasthen extracted with ethyl acetate three times. The combined organicphase was washed with 0.5 N hydrochloric acid (50 mL), 5% sodiumbicarbonate (50 mL), and brine (50 mL). It was then dried over anhydroussodium sulfate and concentrated in vacuo to afford a yellow solid, whichwas purified by recrystallization from ethyl acetatehexane (2080, v/v)to afford a nearly colorless solid (9.15 g, 72%). A secondrecrystallization (ethyl acetatehexane, 1560) afforded a white solid(7.92 g), m.p. 115.3-115.8° C. ¹H NMR (6, CDCl₃): 8.22 (s, 1H),7.78-7.91 (m, 2H), 7.70 (d, J=8.4 Hz, 1H), 7.22-7.45 (m, 5H), 6.99 (s,1H), 4.50-4.71 (m, 1H), 3.96-4.14 (m, 1H), 3.63-3.77 (m, 1H), 3.51 (s,4H), 2.59-3.29 (m, 5H), 2.00-2.18 (m, 1H), 1.40 (s, 9H), 1.06 (d, J=6.4Hz, 3H), 0.96 (d, J=6.4 Hz, 3H). MS 1083 (2MNa)⁺, 553 (MNa)⁺, 431(M-BOC)⁺ and 589 (AcOM)⁻. Purity 96% (HPLC).

Example 2c

To a solution of 36 (2.20 g, 4.26 mmol) in dichloromethane (6 mL) wasadded trifluoroacetic acid (3 mL) at 0° C. The mixture was stirred atroom temperature for 30 min, after which time 20% sodium bicarbonate (20mL) was added. The two phases were separated and the aqueous layer wasextracted three times with ethyl acetate. The combined organic phase waswashed once with brine, dried over anhydrous sodium sulfate and thenconcentrated in vacuo. The residue was purified on silica gel with ethylacetate (0-100%) in hexane as eluant to afford 201 as a white solid(1.23 g, 72%).

A solution of 201 (125 mg, 0.3 mmol, 1.0 equiv.), p-toluenesulfonic acid(19 mg, 0.1 mmol, 0.33 equiv.), and 37% aqueous formaldehyde (112 μL,1.5 mmol, 5.0 equiv.) in THF (3 mL) was stirred at room temperature for3 h, then diluted with ethyl acetate (15 mL). The solution was washedwith 5% sodium bicarbonate once and brine once, then dried overanhydrous sodium sulfate, and concentrated to an oil in vacuo. The crudeproduct 202 was used directly in the next step.

To a solution of 202 in dichloromethane (2 mL) at 0° C. was addedtrifluoroacetic acid (2 mL) and triethylsilane (0.2 mL). The mixture wasstirred at room temperature for 2 h and then quenched with saturatedsodium bicarbonate. This solution was extracted three times with ethylacetate. The combined organic phase was dried over anhydrous sodiumsulfate and concentrated to dryness. The crude product 203 was useddirectly in the next step.

To a solution of 203 in dichloromethane (3 mL) was added triethylamine(84 μL, 0.6 mmol, 2.0 equiv.) and 1.0 M isopropyl chloroformate solutionin toluene (0.45 mL, 0.45 mmol, 1.5 equiv.). The mixture was stirred atroom temperature for 1.5 h and then the solution was mixed with a smallamount of silica gel and evaporated in vacuo to dryness. The residue waspurified on silica gel to afford a white solid, 49 (42 mg, 27% overall).MS 517 (MH)⁺ and 575 (AcOM)⁻. Purity 99% (HPLC).

Example 2d

To a solution of 5 (200 mg, 0.377 mmol) in dichloromethane (1 mL) wasadded trifluoroacetic acid (0.5 mL) at 0° C. The mixture was stirred atroom temperature for 30 min, after which time 20% sodium bicarbonate (10mL) was added. The phases were separated and aqueous layer extractedthree times with ethyl acetate. The combined organic phase was washedonce with brine, dried over anhydrous sodium sulfate and thenconcentrated in vacuo. The crude product (211, 105 mg) was used directlyin the next step.

To a solution of 211 in dichloromethane (2 mL) was added triethylamine(68 μL, 0.448 mmol, 2.0 equiv.) and 1.0 M isopropyl chloroformatesolution in toluene (0.37 mL, 0.366 mmol, 1.5 equiv.). The mixture wasstirred at room temperature for 1.5 h and a small amount of silica gelwas added. Then the solution was evaporated to dryness in vacuo. Theresidue was purified on silica gel (0-40% ethyl acetate in hexane) toafford a white solid, 212 (90 mg, 71%). MS 517 (MH)⁺ and 575 (AcOM)⁻.Purity>99% (HPLC).

To a solution of 212 (61 mg, 0.118 mmol, 1.0 equiv.) in THF (1 mL) wasadded potassium tert-butoxide (53 mg, 0.473 mmol, 4.0 equiv.). After themixture was stirred at room temperature for 30 min, methyl iodide (29μL, 0.473 mmol, 4.0 equiv.) was added. The reaction was stirredovernight and then quenched with methanol. The solution was mixed with asmall amount of silica gel and concentrated to dryness and the residuewas purified on silica gel (0-40% ethyl acetate in hexane) to afford 4(33 mg, 53%). MS 1083 (2MNa)⁺, 531 (MH)⁺ and 567 (MCl)⁻. Purity>99%(HPLC).

Example 2e

To an ice-cooled solution of Boc-L-phenylalaninol (2.51 g, 10.0 mmol,1.0 equiv.) in dichloromethane (40 mL) were added triethylamine (2.1 mL,15.0 mmol, 1.5 equiv.) and methanesulfonyl chloride (1.2 mL, 15 mmol,1.5 equiv.). The reaction mixture was stirred for 30 min at 0° C. then30 min at room temperature. The organic phase was washed consecutivelywith brine, 1M HCl, brine, 5% aqueous NaHCO_(n), and brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford the mesylate as a yellow oil (221), which was used directly inthe next step.

221 was dissolved in DMF (20 mL), and sodium cyanide (1.2 g, 25 mmol,2.5 equiv.) was added. The reaction mixture was heated to 60° C. andstirred for 3 h. After cooling to room temperature, water (120 mL) wasadded and the precipitate was collected and washed with water twice anddried in vacuo overnight. The solid was chromatographed (0-50% ethylacetate in hexane) on silica gel to afford 222 as a white solid (0.6 g,23% yield for the two steps). 222 (104 mg, 0.4 mmol, 1.0 equiv.) andcobaltous chloride hexahydrate (190 mg, 0.8 mmol, 2.0 equiv.) weredissolved in methanol and sodium borohydride (151 mg, 4.0 mmol, 10equiv.) was added in portions with stirring at 0° C. Evolution ofhydrogen gas and then a black precipitate was observed during theaddition. When the addition was complete, stirring was continued for 1hour at room temperature. Then the reaction was quenched by the additionof 1.0 M aqueous HCl (6 mL). The mixture was stirred until the blackprecipitate was dissolved. After the removal of methanol in vacuo andunreacted starting material by extraction with ether, the aqueous layerwas made alkaline with concentrated ammonium hydroxide and extractedwith ethyl acetate three times. The combined organic phase was washedtwice with brine, dried over anhydrous sodium sulfate, and concentrated.Crude 223 (79.4 mg) was used directly in the next step.

To a solution of 223 (79 mg, 0.3 mmol, 1.0 equiv.) in methanol (3 mL)were added sodium acetate (54 mg, 0.66 mmol, 2.2 equiv.), acetic acid(38 μL, 0.66 mmol, 2.2 equiv.) and isobutyraldehyde (60 μL, 0.66 mmol,2.2 equiv.). The mixture was stirred and treated with sodium borohydride(50 mg, 1.32 mmol, 4.4 equiv.). After the reaction solution was stirredfor 30 min at room temperature, 20% aqueous NaHCO_(n) was added. Thereaction mixture was extracted with ethyl acetate three times and thecombined organic phase was washed with brine twice, dried over anhydroussodium sulfate and concentrated in vacuo to afford crude 224 (92 mg),which was used directly in the next step.

To a solution of 224 (45 mg, 0.14 mmol, 1.0 equiv.) in dichloromethane(1.5 mL) was added benzofuran-5-sulfonyl chloride (46 mg, 0.21 mmol, 1.5equiv.) and triethylamine (39 μL, 0.28 mmol, 2.0 equiv.). The mixturewas stirred at room temperature for 1 h and then the solution was mixedwith a small amount of silica gel and evaporated in vacuo to dryness.The residue was chromatographed on silica gel to afford 11 as a whitesolid, (26 mg, 38%). MS 1023 (2MNa)⁺, 401 (M-Boc)⁺ and 559 (AcOM)⁻.Purity>99% (HPLC).

Example 2f

Boc-L-phenylalaninol (1.01 g, 4.0 mmol, 1.0 equiv.) andp-toluenesulfonyl chloride (0.92 g, 4.8 mmol, 1.2 equiv.) were dissolvedin dichloromethane (20 mL) and to the solution was added triethylamine(0.84 mL, 6.0 mmol, 1.5 equiv.) at room temperature. The resultingmixture was stirred for 3 h, and then the reaction was quenched withsaturated ammonium chloride solution. The phases were separated and thewater layer was extracted with ether twice. The combined organic phasewas washed once with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was chromatographed on silica gel(0-20% ethyl acetate in hexane) to afford 231 as a white solid (0.61 g,38%). Purity 99% (HPLC).

231 (261 mg, 0.64 mmol, 1.0 equiv.) was dissolved in DMF (1.5 mL), andsodium azide (84 mg, 1.28 mmol, 2.0 equiv.) was added. The reactionmixture was heated to 80° C. and stirred for 3 h. After cooling to roomtemperature, the solution was partitioned between water (5 mL) and ethylacetate (10 mL). The organic phase was washed with 1N HCl, 5% NaHCO_(n),and water, dried over anhydrous sodium sulfate and then concentrated invacuo. The residue was chromatographed on silica gel to afford 232 as awhite solid (87 mg, 49%). Purity 99% (HPLC). 232 (87 mg, 0.31 mmol)dissolved in ethyl acetate (3 mL) was hydrogenated at atmosphericpressure for 1 h in the presence of 10% PdC (20 mg). The catalyst wasremoved by filtration through Celite, and the filtrate was concentratedin vacuo to give 233, which was used directly in the next step.

To a solution of 233 in methanol (3 mL) were added sodium acetate (49mg, 0.60 mmol, 2.0 equiv.), acetic acid (34 μL, 0.60 mmol, 2.0 equiv.)and isobutyraldehyde (55 μL, 0.60 mmol, 2.0 equiv.). The mixture wasstirred and treated with sodium borohydride (45 mg, 1.2 mmol, 4.0equiv.). After 30 min at room temperature, 20% NaHCO_(n) was added toquench the reaction. The reaction mixture was extracted with ethylacetate three times and the combined organic phase was washed with brinetwice, dried over anhydrous sodium sulfate and concentrated in vacuo togive 234, which was used directly in the next step.

To a solution of 234 in dichloromethane (3 mL) was addedbenzofuran-5-sulfonyl chloride (97 mg, 0.45 mmol, 1.5 equiv.) andtriethylamine (84 μL, 0.60 mmol, 2.0 equiv.). The mixture was stirred atroom temperature for 1 h and then the solution was concentrated invacuo. Preparative TLC (30% ethyl acetate in hexane) afforded 15 as awhite solid (14 mg, yield 10% overall). MS 995 (2MNa)⁺, 509 (MNa)⁺, 387(M-Boc)⁺, 545(AcOM)⁻, and 485 (M-H)⁻. Purity 97% (HPLC).

Example 2g

Boc-L-Dab(Z)-OH DCHA (534 mg, 1.0 mmol, 1.0 equiv.) was dissolved in THF(6 mL), cooled to 0° C., and treated with triethylamine (210 μL, 1.5mmol, 1.5 equiv.) and ethyl chloroformate (114 μL, 1.2 mmol, 1.2equiv.). The resulting mixture was stirred at 0° C. for 30 min andfiltered. The filtrate was added dropwise to a slurry of sodiumborohydride (190 mg, 5.0 mmol, 5.0 equiv.) in water (6 mL) at 0° C.After 4 h, the mixture was diluted with brine and extracted with ethylacetate. The combined organic phase was dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was chromatographed onsilica gel using 0-75% ethyl acetate/dichloromethane as eluant to afford241 as a white solid (170 mg, 50%). Purity 99% (HPLC).

To a solution of 241 (170 mg, 0.5 mmol) in ethanol (5 mL) was added 10%PdC (30 mg). A hydrogen balloon was connected to the reaction vessel.After the system was fully flushed with hydrogen, the reaction mixturewas stirred at room temperature for 4 h, and then filtered throughCelite and concentrated in vacuo to give 97 mg of 242, which was useddirectly in the next step.

To a solution of 242 (45 mg, 0.22 mmol, 1.0 equiv.) in methanol (2 mL)were added sodium acetate (36 mg, 0.44 mmol, 2.0 equiv.), acetic acid(25 pt, 0.44 mmol, 2.0 equiv.) and isobutyraldehyde (40 μL, 0.44 mmol,2.0 equiv.). The mixture was stirred and treated with sodium borohydride(33 mg, 0.88 mmol, 4.0 equiv.). After the reaction solution was stirredfor 30 min at room temperature, 20% NaHCO_(n) was added. The reactionmixture was extracted with ethyl acetate three times and the combinedorganic phase was washed with brine twice, dried over anhydrous sodiumsulfate and concentrated in vacuo to give 243, which was used directlyin the next step.

To a solution of 243 in dichloromethane (2 mL) was addedbenzofuran-5-sulfonyl chloride (65 mg, 0.30 mmol, 1.5 equiv.) andtriethylamine (56 pt, 0.40 mmol, 2.0 equiv.). The mixture was stirred atroom temperature for 1 h and then the solution was concentrated invacuo. The residue was chromatographed on silica gel to afford 244 as awhite solid (39 mg, 38% for the three steps). MS 903 (2MNa)⁺, 463(MNa)⁺, 341 (M-Boc)⁺ and 499 (AcOM)⁻. Purity>99% (HPLC).

To a solution of 244 (36 mg, 0.082 mmol, 1.0 equiv.) in THF (1 mL) wasadded benzyl bromide (39 μL, 0.327 mmol, 4.0 equiv.) and sodium hydride(13 mg, 0.327 mmol, 4.0 equiv.) at 0° C. The mixture was stirred for 2 hwhile the reaction temperature was allowed to gradually return toambient temperature. Then the reaction was quenched with methanol. Thesolution was mixed with a small amount of silica gel and concentrated invacuo and the residue was chromatographed on silica gel (0-50% ethylacetate in hexane) to afford a white solid, 12 (22 mg, 51%). MS 1083(2MNa)⁺, 553 (MNa)⁺, 431 (M-Boc)⁺ and 589 (MOAc)⁻. Purity>99% (HPLC).

Example 2h

To a solution of N-Boc-1,3-diaminopropane (6.97 g, 40 mmol, 1.0 equiv.)in anhydrous 1,2-dichloroethane (160 mL) was added isobutyraldehyde(3.03 g, 42 mmol, 1.05 equiv.) and acetic acid (2.3 mL, 40 mmol, 1.0equiv.). The solution was stirred for 10 min, and then was treated withsodium triacetoxyborohydride (12.72 g, 60 mmol, 1.5 equiv.). Theresulting mixture was stirred for 1 h and then the reaction was quenchedwith 20% aqueous NaHCO_(n) (100 mL) and ethyl acetate (200 mL). Thelayers were separated and the organic phase was washed twice with brine,dried over anhydrous Na₂SO₄, and concentrated in vacuo to afford crude251, which was used directly in the next step.

To a solution of 251 (40 mmol, 1.0 equiv.) in dichloromethane (200 mL)was added benzofuran-5-sulfonyl chloride (10.4 g, 48 mmol, 1.2 equiv.)and triethylamine (8.4 mL, 60 mmol, 1.5 equiv.). The mixture was stirredat room temperature for 2 h and then the reaction was quenched by theaddition of 1M HCl solution (100 mL) and ethyl acetate (200 mL). The twophases was separated and the organic layer was washed with brine twice,dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue waspurified on silica gel with ethyl acetatehexane (13) as eluant to afforda colorless oil, 252 (5.62 g, 34% overall). MS 433 (MNa)⁺, 311 (M-Boc)⁺and 469 (AcOM)⁻. Purity>99% (HPLC).

To a solution of 252 (5.6 g, 13.7 mmol, 1.0 equiv) in anhydrous THF (70mL) was added potassium tert-butoxide (3.07 g, 27.3 mmol, 2.0 equiv.)immediately followed by benzyl bromide (2.4 mL, 20.5 mmol, 1.5 equiv.).The resulting mixture was stirred at room temperature for 1 h, afterwhich time the reaction was quenched by the addition of 1M HCl solutionand ether. The two phases were separated and the water layer wasextracted twice with ether. The combined organic phase was washed twicewith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified on silica gel with ethyl acetatehexane (16) aseluant to afford 19 as a colorless oil (6.5 g, 95%). ¹H NMR (6, CDCl₃):8.19 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.69 (d, J=8.7 Hz,1H), 7.22-7.45 (m, 5H), 6.98 (s, 1H), 4.50 (s, 2H), 3.05-3.30 (m, 4H),2.96 (d, J=7.4 Hz, 2H), 1.75-1.94 (m, 3H), 1.55 (s, 9H), 0.99 (d, J=6.6Hz, 6H). MS 523 (MNa)⁺, and 401 (M-Boc). Purity>99% (HPLC).

Example 2i

To a solution of benzofuran-5-carbaldehyde (146 mg, 1.0 mmol, 1.0equiv.) in anhydrous 1,2-dichloroethane (5 mL) was addedN-Boc-1,3-diaminopropane (192 μL, 1.1 mmol, 1.1 equiv.) and acetic acid(57 μL, 1.0 mmol, 1.0 equiv.). The solution was stirred for 10 min, andthen was treated with sodium triacetoxyborohydride (297 mg, 1.4 mmol,1.4 equiv.). The resulting mixture was stirred for 3 h at roomtemperature and then the reaction was quenched with the addition ofsaturated aqueous NaHCO_(n) solution. The aqueous layer was extractedwith ethyl acetate three times and the combined organic phase was washedtwice with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuoto afford crude 253 (287 mg), which was used directly in the next step.

To a solution of 253 (96 mg, 0.32 mmol, 1.0 equiv.) in dichloromethane(1 mL) was added isobutyryl chloride (34 μL, 0.32 mmol, 1.0 equiv.) andtriethylamine (49 μL, 0.35 mmol, 1.1 equiv.). The mixture was stirred atroom temperature for 1 h and then the reaction solution was transferredvia syringe onto a preparative silica gel TLC plate. The plate waseluted with 1:3 ethyl acetatehexane to give 105 mg (88%) 132, MS 771(2MNa)⁺, 397 (MNa)⁺, 375 (MH)⁺, 275 (M-Boc)⁺. HPLC purity>99%.

132 (38 mg, 0.1 mmol, 1.0 equiv) and sodium hydride (60% dispersion inmineral oil, 8 mg, 0.2 mmol, 2.0 equiv.) were dissolved in anhydrousDMSO (0.5 mL). The solution was stirred at room temperature for 5 min.and then was treated with isobutyl bromide (24 μL, 0.22 mmol, 2.2equiv.). The mixture was heated to 60° C. and stirred for 1.5 h and thenreturned to room temperature. An additional portion of sodium hydride (8mg, 0.2 mmol, 2.0 equiv.) was introduced and 5 minutes later anadditional portion of isobutyl bromide (24 μL, 0.22 mmol, 2.2 equiv.).The resulting mixture was heated to 60° C. and stirred for an additional1.5 h and the reaction then quenched with methanol. The final solutionwas transferred via syringe onto a preparative silica gel TLC plate. Theplate was eluted with 1:4 ethyl acetatehexane to give 15 mg (35%) 133.MS 883 (2MNa)⁺, 453 (MNa)⁺, 431 (MH)⁺ and 331 (M-Boc)⁺. HPLC purity>99%.

Example 2j

To a solution of benzofuran-5-ylmethylamine (147 mg, 1.0 mmol, 1.0equiv.) in dichloromethane (10 mL) were added sequentially water (10mL), Boc-P-Ala-OH (208 mg, 1.1 mmol, 1.1 equiv.) and HOBT (149 mg, 1.1mmol, 1.1 equiv.). The mixture was then cooled in an ice bath to 0-5°C., and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(EDCI) (211 mg, 1.1 mmol, 1.1 equiv.) was added. The resulting mixturewas then stirred overnight at room temperature. The reaction wasquenched with saturated aqueous NaHCO_(n) solution. The aqueous phasewas extracted with ethyl acetate three times and the combined organicphase was dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified using medium pressure chromatography (ethylacetatehexane gradient, 0-100%) to afford 258 mg (81%) 134 as a whitesolid, MS 659 (2MNa)⁺, 341 (MNa)⁺, 319 (MH)⁺, and 377. HPLC purity>99%.

134 (48 mg, 0.15 mmol, 1.0 equiv) and sodium hydride (60% dispersion inmineral oil, 12 mg, 0.3 mmol, 2.0 equiv.) were added to anhydrous DMSO(0.7 mL). The solution was stirred at room temperature for 10 min andthen treated with isobutyl bromide (33 pt, 0.30 mmol, 2.0 equiv.). Themixture was then heated to 60° C. and stirred for 1 h and then returnedto room temperature. An additional portion of sodium hydride (12 mg, 0.3mmol, 2.0 equiv.) was introduced and 5 minutes later an additionalportion of isobutyl bromide (33 μL, 0.30 mmol, 2.0 equiv.). Theresulting mixture was heated to 60° C. and stirred for 1 h and thenreturned to room temperature and quenched with methanol. The finalsolution was transferred onto a preparative silica gel TLC plate viasyringe. The plate was eluted with 1:3 ethyl acetatehexane to give 3.0mg 135 (5%). MS 883 (2MNa)⁺, 453 (MNa)⁺, 431 (MH)⁺ and 331 (M-Boc)⁺.HPLC purity>99%.

Variations, modifications, and other implementations of what isdescribed herein will occur to those of ordinary skill in the artwithout departing from the spirit and the scope of the technology.Accordingly, the technology is not to be limited only to the precedingillustrative descriptions.

1-25. (canceled)
 26. A method of inhibiting cytochrome P450monooxygenase comprising administering to a patient a compoundrepresented by a formula:X-A-B-X′ wherein: X is a lipophilic group containing from 1 to 12 carbonatoms optionally containing from 1 to 3 heteroatoms independentlyselected from the group consisting of O, S, and N, A is selected fromthe group consisting of a bond, —OCON(R2)-, —S(O)_(n)N(R2)-, —CON(R2)-,—COCO(NR2)-, —N(R2)CON(R2)-, —N(R2)S(O)_(n)N(R2)-, N(R2)CO or—N(R2)COO—; B is —(CG₁G₂)_(m)-, wherein m is 0-6 and wherein G₁ and G₂are the same or different and wherein each G₁ and G₂ independently isselected from the group consisting of a bond, H, halo, haloalkyl, OR,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aralkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, and optionally substituted heterocycloalkylwherein each optional substitution independently is selected from thegroup consisting of alkyl, halo, cyano, CF₃, OR, C₃-C₇ cycloalkyl, C₅-C₇cycloalkenyl, R6, OR2, SR2, N(R2)₂, OR3, SR3, NR2R3, OR6, SR6, andNR2R6, and wherein G₁ and G₂, together with the atoms to which they areattached, optionally may form a 3-7-membered carbocyclic or heterocyclicring containing up to three heteroatoms selected from the groupconsisting of N, S and O, and wherein said ring optionally may besubstituted with up to 3 R7 moieties, X′ is

wherein M is selected from the group consisting of: a bond, OC(R8)_(q),—CO—, —SO—, —O—, —O—CO—, —N(D)-SO—, —N(D)-CO—, —N(D)-(R8)_(q)-,—N(CO-D)-(R8)_(q)-, —N(SO_(n)-D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or—CO_(n)—N(D)-(R8)_(q)-, wherein M can be linked in either orientationwith respect to the benzofuran ring, wherein D is selected fromhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkylor aralkyl, O-alkyl, O-cycloalkyl, O-cycloalkylalkyl,O-heterocycloalkyl, O-heterocycloalkylalkyl, O-heteroaralkyl, O-aralkyl,N(R2)-alkyl, N(R2)-cycloalkyl, N(R2)-cycloalkylalkyl,N(R2)-heterocycloalkyl, N(R2)-heterocycloalkylalkyl,N(R2)-heteroaralkyl, and N(R2)-aralkyl, wherein D optionally issubstituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl; wherein Ris H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl; wherein each R2 is independentlyselected from the group consisting of H, C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl eachfurther optionally substituted with one or more substituents selectedfrom the group consisting of C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclo, halo, OR, ROH, R-halo, NO₂,CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂,N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R,NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂,═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and ═NNRS(O)_(n)(R); or each R2 isindependently selected from the group consisting of C₁-C₆ alkyl;substituted by aryl or heteroaryl; which groups optionally aresubstituted with one or more substituents selected from the groupconsisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR; R3 is C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, orheterocyclo; which groups optionally are substituted with one or moresubstituents selected from the group consisting of halo, OR2, R2-OH,R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2,C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2,NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, oxo, ═N—OR2,═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂, ═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂,and ═NNR2S(O)_(n)(R2); R6 is aryl or heteroaryl, wherein said aryl orheteroaryl optionally is substituted with one or more groups selectedfrom the group consisting of aryl, heteroaryl, R2, R3, halo, OR2, R2OH,R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2,C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2,NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, OC(O)R2, OC(S)R2,OC(O)N(R2)₂, and OC(S)N(R2)₂; R7 is H, oxo, C₁-C₁₂ alkyl; C₃-C₈cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocycloalkyl, each further optionally substituted with one or moresubstituents selected from the group consisting of C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclo; halo, OR,ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂,SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂,N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR,═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and ═NNRS(O)_(n)(R); R8is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl; wherein n=1-2, and q=0-1, wherein thebenzene ring of the benzofuran moiety optionally is substituted by up tothree substituents independently selected from the group consisting ofR2, halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂,SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, and NRPO_(n)OR, whereinsaid up to three substituents do not form a ring between any adjacentcarbon atoms of said benzene ring, and with the proviso that saidcompound does not contain a basic aliphatic amine function and does notcontain a carboxylic acid group, and provided that: when X is a 5-7membered non-aromatic monocyclic heterocycle, optionally fused orbridged with one or more 3-7 membered non-aromatic monocyclicheterocycle to form a polycyclic system, wherein any of saidheterocyclic ring systems contains one or more heteroatoms selected fromO, N, S, and P, and when B is

wherein U is selected from optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted cycloalkyl, or optionallysubstituted aralkyl, then J cannot be —N(D)-SO_(n)— or —N(D)-CO_(n). 27.The method according to claim 26, wherein the compound is administeredprior to, and/or substantially contemporaneously with, a drug whereinefficacy of said drug is compromised due to degradation by cytochromeP450 monooxygenase.
 28. The method according to claim 26, wherein thedrug is selected from the group consisting of Cyclosporine, Tacrolimus(FK506), Sirolimus (rapamycin), Indinavir, Ritonavir, Saquinavir,Felodipine, Isradipine, Nicardipine, Nisoldipine, Nimodipine,Nitrendipine, Nifedipine, Verapamil, Etoposide, Tamoxifen, Vinblastine,Vincristine, Taxol, Atorvastatin, Fluvastatin, Lovastatin, Pravastatin,Simvastatin, Terfenadine, Loratadine, Astemizole, Alfentanil,Carbamazepine, Azithromycin, Clarithromycin, Erythromycin, Itraconazole,Rifabutin, Lidocaine, Cisapride, Sertraline, Pimozide, Triazolam,Anastrazole, Busulfan, Corticosteroids (dexamethasone, methylprednisoneand prednisone), Cyclophosphamide, Cytarabine, Docetaxel, Doxorubicin,Erlotinib, Exemestane, Gefitinib, Idarubicin, Ifosphamide, Imatinibmesylate, Irinotecan, Ketoconazole, Letrozole, Paclitaxel, Teniposide,Tretinoin, Vinorelbine, quinidine, alprazolam, diazepam, midazolam,nelfinavir, chlorpheniramine, amlodipine, diltiazem, lercanidipine,cerivastatin, estradiol, hydrocortisone, progesterone, testosterone,alfentanyl, aripiprazole, cafergot, caffeine, cilostazol, cocaine,codeine, dapsone, dextromethorphan, domperidone, eplerenone, fentanyl,finasteride, gleevec, haloperidol, irinotecan, Levo-Alpha AcetylMethadol (LAAM), methadone, nateglinide, odansetron, propranolol,quinine, salmeterol, sildenafil, trazodone, vincristine, zaleplon,zolpidem, ixabepilone, Agenerase (APV), Aptivus (TPV), Crixivan (IDV),Invirase (SQV), Lexiva (FPV), Prezista (DRV), Reyataz (ATV) Viracept(NFV), Elvitegravir, Selzentry, Vicriviroc, Telaprevir, Telithromycin,tandospirone or buspirone.
 29. A compound represented by a formula:X-A-B-X′ wherein: X is a lipophilic group containing from 1 to 12 carbonatoms optionally containing from 1 to 3 heteroatoms independentlyselected from the group consisting of O, S, and N, A is —OCON(R2)-,—S(O)_(n)N(R2)-, —CON(R2)-, —COCO(NR2)-, —N(R2)CON(R2)-,—N(R2)S(O)_(n)N(R2)-, N(R2)CO or —N(R2)COO—; B is (CG₁G₂)_(m)-, whereinm is 2-6 and wherein G₁ and G₂ are the same or different and whereineach G₁ and G₂ independently is selected from the group consisting of abond, H, halo, haloalkyl, OR, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aralkyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyl, andoptionally substituted heterocycloalkyl wherein each optionalsubstitution independently is selected from the group consisting ofalkyl, halo, cyano, CF₃, OR, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, R6,OR2, SR2, N(R2)₂, OR3, SR3, NR2R3, OR6, SR6, and NR2R6, and wherein G₁and G₂, together with the atoms to which they are attached, optionallymay form a 3-7-membered carbocyclic or heterocyclic ring containing upto three heteroatoms selected from the group consisting of N, S and O,and wherein said ring optionally may be substituted with up to 3 R7moieties, X′ is

wherein J is selected from: —N(D)-SO_(n)—, —N(D)-CO—, —N(D)-(R8)_(q)-,—N(CO-D)-(R8)_(q)-, —N(SO_(n)-D)-(R8)_(q)-, —SO_(n)—N(D)-(R8)_(q)-, or—CO_(n)—N(D)-(R8)_(q)-, wherein D is selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyl or aralkyl,O-alkyl, O-cycloalkyl, O-cycloalkylalkyl, O-heterocycloalkyl,O-heterocycloalkylalkyl, O-heteroaralkyl, O-aralkyl, N(R2)-alkyl,N(R2)-cycloalkyl, N(R2)-cycloalkylalkyl, N(R2)-heterocycloalkyl,N(R2)-heterocycloalkylalkyl, N(R2)-heteroaralkyl, N(R2)-aralkyl, whereinD optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl, orS-alkyl; wherein R is H, alkyl, haloalkyl, alkenyl, alkynyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein each R2is independently selected from the group consisting of H, C₁-C₁₂ alkyl,C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, andheterocycloalkyl each further optionally substituted with one or moresubstituents selected from the group consisting of C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclo; halo, OR,ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂,SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂,N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR,═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and ═NNRS(O)_(n)(R); oreach R2 is independently selected from the group consisting of C₁-C₆alkyl; substituted by aryl or heteroaryl; which groups optionally aresubstituted with one or more substituents selected from the groupconsisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR; R3 is C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, orheterocyclo; which groups optionally are substituted with one or moresubstituents selected from the group consisting of halo, OR2, R2-OH,R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2,C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2,NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, oxo, ═N—OR2,═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂, ═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂,and ═NNR2S(O)_(n)(R2); R6 is aryl or heteroaryl, wherein said aryl orheteroaryl optionally are substituted with one or more groups selectedfrom the group consisting of aryl, heteroaryl, R2, R3, halo, OR2, R2OH,R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2,C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2,NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, OC(O)R2, OC(S)R2,OC(O)N(R2)₂, and OC(S)N(R2)₂; R7 is H, oxo, C₁-C₁₂ alkyl; C₃-C₈cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocycloalkyl, each further optionally substituted with one or moresubstituents selected from the group consisting of C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclo; halo, OR,ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂,SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂,N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR,═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and ═NNRS(O)_(n)(R); R8is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl; wherein n=1-2, and wherein q=0-1,provided that: when X is a 5-7 membered non-aromatic monocyclicheterocycle, optionally fused or bridged with one or more 3-7 memberednon-aromatic monocyclic heterocycle to form a polycyclic system, whereinany of said heterocyclic ring systems contains one or more heteroatomsselected from O, N, S, and P, and when B is

wherein U is selected from optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted cycloalkyl, or optionallysubstituted aralkyl, then J cannot be —N(D)-SO_(n)— or —N(D)-CO_(n)—.30. The compound according to claim 29, wherein X is selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl; wherein X optionally is substitutedwith one or more substituents selected from the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclo; halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR,═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and═NNRS(O)(R).
 31. The compound according to claim 29 wherein X isselected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl,heteroaryl, and heteroaralkyl.
 32. The compound according to claim 29wherein X optionally is substituted with one or more substituentsselected from the group consisting of halo, OR, ROH, R-halo, CN,CO_(n)R, CON(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, oxo, and ═N—OR.
 33. The compound according to claim 29,wherein X optionally is substituted with one or more substituentsselected from the group consisting of halo, OR, CO_(n)R, CON(R)₂,SO_(n)N(R)₂, SO_(n)R, N(R)₂, N(R)CO_(n)R, and oxo.
 34. The compoundaccording to claim 29 wherein G₁ and G₂ are the same or different andindependently are selected from the group consisting of a bond, H, OR,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aralkyl, optionally substituted heteroaryl, andoptionally substituted heteroaralkyl. 35-48. (canceled)
 49. A compoundrepresented by a formula:X-A-B-X′ wherein: X is a lipophilic group containing from 1 to 12 carbonatoms optionally containing from 1 to 3 heteroatoms independentlyselected from the group consisting of O, S, and N, A is selected fromthe group consisting of a bond, —OCON(R2)-, —S(O)_(n)N(R2)-, —CON(R2)-,—COCO(NR2)-, —N(R2)CON(R2)-, —N(R2)S(O)_(n)N(R2)-, N(R2)C0 or—N(R2)COO—; B is —(CG₁G₂)_(m)-, wherein m is 0-6 and wherein G₁ and G₂are the same or different and wherein each G₁ and G₂ independently isselected from the group consisting of a bond, H, halo, haloalkyl, OR,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aralkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, and optionally substituted heterocycloalkylwherein each optional substitution independently is selected from thegroup consisting of alkyl, halo, cyano, CF₃, OR, C₃-C₇ cycloalkyl, C₅-C₇cycloalkenyl, R6, OR2, SR2, N(R2)₂, OR3, SR3, NR2R3, OR6, SR6, andNR2R6, and wherein G₁ and G₂, together with the atoms to which they areattached, optionally may form a 3-7-membered carbocyclic or heterocyclicring containing up to three heteroatoms selected from the groupconsisting of N, S and O, and wherein said ring optionally may besubstituted with up to 3 R7 moieties, X′ is

wherein M is selected from the group consisting of: a bond, OC(R8)_(q),—CO—, —SO_(n)—, -0-, —O—CO—, —N(D)-SO_(n)—, —N(D)-CO_(n)—,—N(D)-(R8)_(q)-, —N(CO-D)-(R8)_(q)-, —N(SO_(n)-D)-(R8)_(q)-,—SO_(n)—N(D)-(R8)_(q)-, or —CO_(n)—N(D)-(R8)_(q)-, wherein M can belinked in either orientation with respect to the benzofuran ring,wherein D is selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl,O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl,O-heteroaralkyl, O-aralkyl, N(R2)-alkyl, N(R2)-cycloalkyl,N(R2)cycloalkylalkyl, N(R2)-heterocycloalkyl,N(R2)-heterocycloalkylalkyl, N(R2)-heteroaralkyl, and N(R2)-aralkyl,wherein D optionally is substituted by alkyl, halo, nitro, cyano,O-alkyl, or S-alkyl; wherein R is H, alkyl, haloalkyl, alkenyl, alkynyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein each R2is independently selected from the group consisting of H, C₁-C₁₂ alkyl,C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, andheterocycloalkyl each further optionally substituted with one or moresubstituents selected from the group consisting of C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclo, halo, OR,ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂,SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂,N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR,═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and ═NNRS(O)_(n)(R); oreach R2 is independently selected from the group consisting of C₁-C₆alkyl; substituted by aryl or heteroaryl; which groups optionally aresubstituted with one or more substituents selected from the groupconsisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R,C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR; R3 is C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, orheterocyclo; which groups optionally are substituted with one or moresubstituents selected from the group consisting of halo, OR2, R2-OH,R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2,C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2,NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, oxo, ═N—OR2,═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂, ═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂,and ═NNR2S(O)_(n)(R2); R6 is aryl or heteroaryl, wherein said aryl orheteroaryl optionally is substituted with one or more groups selectedfrom the group consisting of aryl, heteroaryl, R2, R3, halo, OR2, R2OH,R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2,C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2,NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, OC(O)R2, OC(S)R2,OC(O)N(R2)₂, and OC(S)N(R2)₂; R7 is H, oxo, C₁-C₁₂ alkyl; C₃-C₈cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocycloalkyl, each further optionally substituted with one or moresubstituents selected from the group consisting of C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclo; halo, OR,ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂,SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂,N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR,═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, and ═NNRS(O)_(n)(R); R8is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, and heteroaralkyl; wherein n=1-2, and q=0-1, wherein thebenzene ring of the benzofuran moiety optionally is substituted by up tothree substituents independently selected from the group consisting ofR2, halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂,SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, and NRPO_(n)OR, whereinsaid up to three substituents do not form a ring between any adjacentcarbon atoms of said benzene ring, and with the proviso that saidcompound does not contain a basic aliphatic amine function and does notcontain a carboxylic acid group, and provided that: when X is a 5-7membered non-aromatic monocyclic heterocycle, optionally fused orbridged with one or more 3-7 membered non-aromatic monocyclicheterocycle to form a polycyclic system, wherein any of saidheterocyclic ring systems contains one or more heteroatoms selected fromO, N, S, and P, and when B is

wherein U is selected from optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted cycloalkyl, or optionallysubstituted aralkyl, then J cannot be —N(D)-SO— or —N(D)-CO_(n).
 50. Aformulation comprising a effective amount of a compound according toclaim 29 and a pharmaceutically acceptable diluent, carrier, orexcipient.
 51. A composition comprising an effective amount of acompound according to claim 29 and an effective amount of a drug whereinin vivo efficacy of said drug is compromised due to degradation bycytochrome P450 monooxygenase.
 52. A composition comprising a compoundof claim 29 and an antiretroviral agent. 53-54. (canceled)